TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION, VOL. 127, 2016
THE GORDON WILSON LECTURE EVOLUTION OF CLINICAL CANCER GENETICS JUDY E. GARBER, MD, MPH BOSTON, MASSACHUSETTS
INTRODUCTION The era of cancer genetics may arguably have begun with the cloning of the first cancer susceptibility gene, Rb1, by Stephen Friend and colleagues in 1986(1), but the existence of a tumor suppressor gene was predicted by Knudson based on modeling of the pediatric tumors, retinoblastoma and Wilms’ tumor(2). He found that some tumors were observed to cluster in families, in which they occurred at younger ages, bilaterally in paired organs, multifocally, and repeatedly from generation to generation. The tumors appeared to be the same histologically and in other observable biological features to the sporadic versions, when they occurred as a single event in a family. As these were pediatric tumors, their rarity enhanced these observations as the tumors occurring without family clustering were also uncommon. Knudson proposed that both the sporadic and familial tumors contained mutations in both copies of a specific gene, but that in the familial case, one copy of the gene was mutated in the germline. The fact that the genes, when not mutated, did not permit tumors to develop led to the expectation that these genes would be “tumor suppressor” genes, so that mutating both copies would permit tumor development. The germline mutation in the tumor suppressor gene would confer increased susceptibility to the specific cancers, but at least one additional event would be necessary to mutate the second copy of the tumor suppressor gene, and often additional mutations would also be needed for tumors to develop. In the 30 years since the cloning of Rb1, cancer genetics has exploded, both the somatically altered genes that drive tumors or are passengers that may still affect tumor behavior and the germline susceptibility genes that have made clinical cancer genetics an essential component Correspondence and reprint requests: Judy E. Garber, MD, MPH, Harvard Medical School, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, Tel: 617-632-5770, E-mail: [email protected]. Potential Conflict of Interest: None disclosed.
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of medical oncology today. In this manuscript, we will review some of the more important developments in cancer genetics that have enabled the development of a new field that continues to evolve for the benefit of cancer patients, and increasingly their unaffected relatives, in order to provide opportunities for cancer prevention and sometimes for targeted therapeutics.
PRINCIPLES OF CANCER GENETICS The primary feature of an inherited cancer syndrome is the clustering of cancers in families. Therefore, a detailed family history is essential to the identification of a syndrome. Families tend to know more about maternal than paternal family members and are often aware of only limited details about the health of their relatives, particularly if there were rare diagnoses or if affected individuals were deceased before the index patient was born. The more distant the relationship, the less reliable the information, and sometimes a diagnosis was just not available in the era before sophisticated imaging and the principle of tissue diagnosis for all malignancies. Nonetheless, the principle of obtaining a 3-generation pedigree often provides very helpful information about a clustering of cancers, or at least will provide guidance as to which family members might have a critical diagnosis to be elucidated by medical records or death certificates. Early age at cancer diagnosis is another essential feature. Therefore, childhood cancers or an adenocarcinoma before age 45 or 50 can be a signal, as can a rare cancer diagnosis. Sarcomas occur in 1 in 100,000 in the population, so the presence of a sarcoma with other early onset disease can be a sign, as can breast cancer in men, or bilateral tumors in paired organs (other than ovarian cancer in which bilateral tumors are common). Clinical acumen may lead to the recognition of a pheochromocytoma because of a family history of sudden death, or death during surgery, rather than a specific history of an adrenal tumor. Once a possible predisposition syndrome is suspected, identification of the individual in the family most likely to carry a predisposing mutation, if one is present, is important. Testing an uninformative family member can misdirect the entire evaluation as a negative molecular evaluation may be over-interpreted as exonerating the entire kindred. Sometimes more than one individual will need to be tested, especially if the syndrome involves clustering of common cancers, so that a “phenocopy” may be present—that is, an individual with the same cancer diagnosis but not the same underlying genetic predisposition, just
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a more common sporadic malignancy that looks like it is part of the familial clustering. In Table 1, the features of hereditary cancer syndromes are enumerated. Individuals who present to their physician or a specialty clinic may elect to undergo germline genetic testing, if it is offered by the genetic counselor or other provider performing the assessment. Generally, a pretest counseling session will inform the patient about the specifics of the cancer syndrome and provide information about the mode of inheritance and some specifics of the genetic test; the kind of information the testing will provide; and the risks, benefits, and limitations of that testing. The goal is for the individual to make an informed decision about whether or not he or she is ready to undergo the testing and to deal with the results, or whether they are not interested in this kind of information or prefer to defer their genetic testing. The passing of the Genetic Information Nondiscrimination Act of 2008 by Congress provides for protection against health insurance discrimination on the basis of genetic information, but not against life or disability insurance discrimination. Individuals must consider the issues that may arise if they are found to carry a predisposing mutation and will need to share that information with other family members, not all of whom may be ready to hear about a potential shared risk. The most difficult implication of genetic testing for people to contemplate is the fact that, if they test positive, each of their offspring and siblings has a 50% chance of sharing that mutation, except for rare circumstances, like mosaicism, where siblings do not share the risk. Most insurers do cover genetic testing for people who meet criteria, usually based on family or personal cancer history, but there can be exceptions. Medicare and other public insurers often have more restrictive coverage. Genetic counselors are indispensable in the provision of pretest information, and perhaps even more important in disclosure of results and subsequent discussion, as patients may need assistance in sharing the essentials TABLE 1 Features of Hereditary Cancer Syndromes • • • • • • • • •
ancer in two or more family members in the same lineage C Early age at cancer diagnosis Multiple primary tumors in same individual Bilateral or multiple rare cancers Constellation of tumors consistent with a hereditary cancer syndrome (e.g., Lynch, Cowden) Multiple affected generations Congenital anomalies or associated benign conditions Specific tumor histologies Findings on tumor genotyping
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of complex information with relatives. However, as genetic testing has become more mainstream, different models are being examined in light of the workforce issues that limit the availability of genetic counselors, so that nurses, physicians, and online materials are taking on portions of their roles. The goal is for individuals to embrace the fact that most cancer genetic testing can either be reassuring (they test negative) or provide information they can use to obtain the proper care. Such care may often help them to avoid a cancer diagnosis or at least have early diagnosis when cure is more likely. Anxiety is often an issue, but in many studies, early sadness and anxiety is replaced by empowerment for most people. However, many still struggle with the repeated screening studies and challenges of having family members deal with testing, care, or cancers.
MEN2 Most, but not all, inherited cancer susceptibility syndromes occur because of mutations in tumor suppressor genes. However, syndromes have been identified in which the predisposing gene is an oncogene, inherited in the activated form, and a typical second hit is not necessary. The prototypical example is Multiple Endocrine Neoplasia Type 2 (MEN2), which is attributable to germline mutations in the RET proto-oncogene. There is interesting genotype–phenotype correlation in this gene, with clustering of specific activating mutations by functional region of the gene associated with full MEN2A, or familial medullary thyroid carcinoma only, or MEN2B, or finally, conversely, inactivating mutations associated with Hirschsprung’s disease. The latter is not a cancer predisposition syndrome at all but rather a syndrome of the congenital absence of ganglion cells from the colon(3). Testing for germline mutations in RET is the standard of care for all cases of medullary thyroid cancer, which could be the first recognized member of the cluster of diagnoses comprising MEN2, or could be a manifestation of the more limited familial medullary thyroid cancer. The importance of screening for germline RET mutations is emphasized by the recommendations for management of mutation carriers, for whom recommendations are to undergo prophylactic thyroidectomy before age 6, because of the very early age at which medullary thyroid cancers have been observed in mutation carriers. Mutation carriers are also screened annually with biochemical screens for pheochromocytoma and hyperparathyroidism. Therefore, genetic testing is recommended for adults and children at or before age 5(3). In addition, it is
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now possible to treat advanced medullary thyroid cancer with protein kinase inhibitors, including Vandetanib(4) and Cabozantinib(5), which inhibit RET activity.
GENETIC HETEROGENEITY Genetic heterogeneity is defined as the phenomenon in which a single phenotype or genetic disorder may be caused by a germline mutation in any of a number of genes. Genetic heterogeneity is commonly observed in cancer genetics. A remarkable example of genetic heterogeneity is observed in pheochromocytomas. The rare tumor type can occur as a single or the first manifestation of inherited endocrine cancer syndromes attributable to germline mutations in RET, as part of MEN2A, in VHL as part of von Hippel Lindau syndrome, and in the SDH complex genes (SDHA, B, C, D, and TMEM127), which code subunits of the mitochondrial complex II. In one series, 25% of individuals with pheochromocytomas collected without regard to family history were found to carry a mutated germline allele in one of the above genes, and that was before all of the SDH genes had been identified(6). In general, about 5 to 10% of tumors are ultimately attributable to a germline predisposing mutation, so the rate of germline mutations among individuals with pheochromocytomas is higher than anticipated and has not yet been duplicated. Pheochromocytomas provide examples of another phenomenon in cancer genetics. Rare tumors and syndromes have often provided a clue to the presence of an inherited predisposition. Childhood cancers are uncommon, partly because children have generally not lived long enough to have been sufficiently exposed to carcinogens that could contribute to tumor development. Recently, large series have identified germline mutations in recognized predisposition genes in only about 10%(7), which is comparable to the prevalence in adult cancer patients as well(8). Other possible explanations for elevated rates of pathogenic germline mutations in series include: (1) erroneous interpretation of sequence variants to include alterations whose functional significance is not clearly deleterious, (2) misclassification of tumor diagnoses, and (3) enrichment of unselected series with cases whose family histories were incompletely ascertained. This can be a particular challenge as many individuals are unaware of the specifics of cancer diagnoses, particularly if a tumor is a rare type, if the affected relative is somewhat distant, or if the parent connected to the branch of the kindred affected with the cancers is deceased(9).
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HEREDITARY COLORECTAL CANCER SYNDROMES Common cancers can also be featured in hereditary cancer predisposition syndromes. Colorectal cancers are components of some of the best known, best characterized but ironically least often recognized syndromes. Approximately 10 to 30% of colorectal cancers are considered familial, or not sporadic. Please refer to a useful comprehensive review(10). Nearly 1% of colon cancers are attributable to Familial Adenomatous Polyposis (FAP) associated with mutations in the tumor suppressor APC gene, as well as one of the few recessive syndromes, MutYH gene mutations, in which the syndrome is termed “MYH-associated polyposis,” or MAP (and requires the affected individuals to have inherited mutations in both copies of MutYH). The rate of new or de novo mutations in APC is 20%, of which about 20% are mosaic. However, once an individual has a mutation, even if de novo (so their siblings may not be at risk), she or he can pass it to offspring. Approximately 95% of individuals will have a molecular diagnosis in the era of analysis of APC by next generation sequencing and analysis of rearrangements by deletions and duplications (Del-Dup), plus MutYH examination. The syndrome includes the classic syndrome of carpets of polyps in the colon, presenting from the teens throughout life, and associated with a nearly 100% risk of colon cancer by age 50. Adenomas can be found in the duodenum and in the small bowel. Other tumors also occur excessively in FAP, including thyroid adenocarcinomas and desmoid tumors. Much of the genetic testing is done in childhood and adolescence, since management of the syndrome can include prophylactic colectomy at young ages. Chemopreventive interventions with NSAIDs and DFMO (difluoromethylornithine) have been examined in several large clinical trials and, while active, have not achieved standard of care status(11). Inherited GI Cancer Syndromes and their Susceptibility Genes Syndrome
Gene(s)
FAP Lynch syndrome Peutz-Jegher syndrome Juvenile polyposis syndrome Cowden syndrome “Proofreading” or hypermutable polyposis
APC, MutYH (recessive) MLH1, MSH2, MSH6, PMS1, PMS2, EpCAM STK11 SMAD, BMPR1A PTEN POLD1, POLE
The most common hereditary GI cancer predisposition syndrome is Lynch syndrome, named for Henry Lynch, one of the giants of cancer
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genetics who first recognized it and whose carefully documented collection of families and specimens enabled the identification of multiple genes conferring predisposition. The “mismatch repair” genes includes MLH1, MSH2, MSH6, and PMS2, which are the “spellcheck” genes repairing small DNA errors, and EpCAM, an unusual gene that is responsible for methylation as a means of inactivation of DNA repair. When these genes are inactivated, the DNA repair leads to a stuttering pattern of erroneous DNA in the resulting tumor tissue called “microsatellite instability (MSI)” which can be detected in a molecular pathology laboratory. Therefore, tumors can be tested to see whether they manifest MSI, and current College of American Pathologists guidelines require that all colorectal and endometrial tumors be tested either for MSI or for inactivation of the proteins made from the genes enumerated above using immunohistochemistry. Although MSI is a hallmark feature associated with Lynch syndrome, approximately 15% of sporadic colorectal cancers have the MSI-high phenotype because of somatic MLH1 promoter hypermethylation, which also can underlie the loss of MLH1 (often with loss of PMS2) in tumors negative for MLH1 by IHC. Testing tumor DNA for the somatic BRAF mutation V600E is routine when MLH1 protein expression is absent, as it correlates with sporadic tumor rather than Lynch syndrome. If none of the alternative mechanisms is suggested by this analysis, then individuals whose tumors manifest MSI or specific protein absence by IHC should be referred for germline genetic testing for Lynch syndrome(10). Lynch syndrome is a relatively common cancer predisposition syndrome, and it is estimated that up to 500,000 carriers exist in the United States, though many are unaware of their status. This is unfortunate, as they have very high lifetime colorectal and endometrial cancer risks, and these cancers can be prevented with early and frequent colonoscopy and prophylactic hysterectomy. Lynch patients do not develop carpets of polyps like FAP, but do develop their adenomatous polyps at an accelerated pace. A colonoscopy every 1 to 2 years is recommended beginning at age 25, and upper endoscopy is added at intervals(12). Because the risk of endometrial cancer is also increased, prophylactic hysterectomy is recommended, as pelvic ultrasound and endometrial biopsies are diagnostic rather than screening procedures and have not been shown to be sufficient to diagnose early disease. The ovaries may also be removed though the risk is not as high as in other syndromes, but effective screening strategies for ovarian cancer do not yet exist. Patients diagnosed with colon or endometrial cancers may have a curable disease, and learning that they have Lynch syndrome through tumor and germline testing can help make sure they do not
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develop additional primary tumors. Relatives should be tested to learn whether they share the altered gene and the associated cancer risks, or do not share the mutation and do not require all of the care(13).
HEREDITARY BREAST-OVARIAN CANCER SYNDROME The clustering of breast cancer in families has long been recognized. The modern era arrived with the mapping of the first breast cancer susceptibility gene, BRCA1, by Mary Claire King and colleagues in 1990. By 1994, BRCA1 had been cloned, and BRCA2 was mapped and cloned shortly thereafter. By 2015, hundreds of thousands of individuals had undergone genetic testing for germline mutations in BRCA1/2, and thousands had contributed data and specimens to research in large consortia, which has enabled more rapid and thorough study of the genetics of hereditary breast-ovarian cancer. The recognition of the prominence of ovarian cancer helped to distinguish the BRCA1/2 families early on, and current data show that mutations in these genes also confer increased risk of male breast cancer, pancreatic cancer, prostate cancer, melanoma, and possibly gastric and other tumors as well. Multiple international screening studies have demonstrated the superior sensitivity of breast MRI to mammograms. Evidence-based guidelines(14) provide recommendations for initiation of breast surveillance with MRI alone at age 25, with the addition of mammograms at age 30, with alternating imaging every 6 months. There is no effective ovarian surveillance at this time, though active research is ongoing. The most important intervention is risk-reducing bilateral salpingo-oophorectomies (RRSO), which is recommended after completion of childbearing at about age 35 to 40. The lifetime ovarian cancer risk is 40-to 60% in BRCA1 and 15 to 20% in BRCA2, with population risk in the range of 1.3%. RRSO has been shown to reduce the risk of ovarian cancer by more than 90%, and to reduce breast cancer risk as well. Moreover, RRSO has been shown to reduce both ovarian and breast cancer mortality in carriers(15). Bilateral mastectomies are discussed as an option for carriers, with recognition that a decision to proceed to surgery is a very individual one. However, the rates of mastectomies have been rising as reconstruction options have improved, with the more frequent use of nipple-sparing and autologous tissue procedures, as well as novel approaches to implant reconstruction. Hormone replacement has been shown to be safe after RRSO, even in women who retain their breasts, though the data are not ideal. Oral contraceptives have
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been shown to reduce or delay ovarian cancer risk in both BRCA1 and BRCA2 carriers, with no effect on breast cancer risk in BRCA1 carriers, and a small increase in BRCA2 carriers(16). The BRCA1 and BRCA2 genes have been shown to have multiple and critical roles in DNA repair. Clearly, carriers of a single mutation have basically normal physiology and are able to reproduce, but their tumors are known to have generally lost the second copy of the involved gene and then to have significant defects in DNA repair. The defects include problems with the repair of double strand breaks in particular. Recognition of the mechanism of action of these genes led to the observation that first BRCA2 and later BRCA1 could occur in rare individuals as compound heterozygous mutations—that is, an individual with both copies of the gene containing a mutation in the germline. The clinical manifestation was a form of Fanconi anemia, and the recognition of this link by D’Andrea and colleagues permitted the evaluation of the multiple other genes identified in the Fanconi anemia pathway of DNA repair, all of which have been shown to confer increased risk of breast or other cancers, though often with more moderate risk, when present as a heterozygous mutation (17,18). It is now possible to test for germline mutations in these genes as well as BRCA1/2, enabling identification of the underlying mutations in families in whom BRCA1/2 testing was negative, despite the presence of the clinical features suggesting the presence of an underlying predisposition. The other important result of the understanding of the role of BRCA1/2 and related genes in DNA repair has been the development of therapies that target the associated deficiencies. For example, the platinum salts, cis- and carboplatin (though not all platinum compounds), are known to create DNA-cross links that require intact double strand break repair to excise(19). Because BRCA1/2 tumor cells lack intact double strand break repair, the tumor cells in which both copies of the BRCA1 or BRCA2 genes are absent have been shown to often be more vulnerable to killing by the platinum salts. Examples include triple negative breast cancer in BRCA carriers and ovarian cancer, for which carboplatin is a backbone of treatment. In ovarian cancer, for example, individuals who carry a BRCA2 mutation have a superior survival, perhaps mediated by the enhanced response to platinum therapy(20). In addition, the PARP inhibitors, novel therapies targeting a specific DNA repair protein, PARP1, are in development. At this time, a single PARP inhibitor is approved for treatment of women with a germline BRCA1/2 mutation who have recurrent ovarian cancer. These drugs are in clinical trials in women with mutations and recurrent breast
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cancer, as well as in a large international adjuvant therapy clinical trials in women with a germline BRCA mutation in breast cancer at time of diagnosis. The drugs are in trials in combination with immunotherapies and other agents, and also beyond breast and ovarian cancer. For example, in a trial in men with metastatic castrate resistant prostate cancer, response to PARP inhibitor was predicted by germline or somatic mutation in the BRCA1/2 genes or associated DNA repair genes(21). Recent work identified an 11% prevalence of germline BRCA2 and related DNA repair genes in men with diagnosis of this aggressive tumor(22). Trials are also in progress in the treatment of pancreatic cancer among BRCA1/2 carriers.
LI FRAUMENI SYNDROME In 1969, Li and Fraumeni published their landmark paper in which they questioned whether a clustering of a diverse group of tumors in a single family could be the result of a single predisposing mutation. Most cancer predisposition syndromes at that time featured predominantly a single cancer. Of course, eventually most predisposition syndromes have been shown to include more than one tumor type, but Li Fraumeni is still notable for the extent of diversity of early onset cancers, with excessive incidence of sarcomas, adrenal cortical carcinomas, breast cancers, brain tumors, and very early onset of a spectrum of adenocarcinomas. Germline mutations in the TP53 gene have been shown to account for the great majority of classic Li Fraumeni families, at least 70%. Families can be devastated by this syndrome, with cancer deaths among children and young adults occurring excessively, and multiple primary tumors particularly common in individuals with Li Fraumeni syndrome. Data suggesting enhanced carcinogenic effects of therapeutic radiation among carriers have led to recommendations to avoid therapeutic radiation in carriers to the extent possible. Recent data have raised the question of whether there could be a broader spectrum of Li Fraumeni syndrome, including some with less penetrant forms, such as individuals whose TP53 mutation was found on expanded genetic testing which looks at a panel of 20 or more susceptibility genes rather than a single gene at a time. Many of these individuals appear to have cancer histories that are not as dramatic as some of the patients whose family configurations have led to targeted TP53 mutation testing. This is currently under study. A recent review provides detailed information about LFS(23).
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NEW CHALLENGES AND OPPORTUNITIES As technologies advance, new capacities introduce new challenges. For example, many novel therapeutic strategies target specific somatic mutations in particular genes in tumors. Therefore, it is becoming the standard of care to biopsy tumors to document metastatic disease and to characterize the mutation spectrum to look for therapeutic targets(24). Examination of the germline DNA in that setting may take place primarily to “subtract out” those mutations and leave the acquired somatic “driver” mutations. However, results of the testing may identify mutations that should be examined in the germline when they involve BRCA1 or other DNA repair genes, or Lynch syndrome or other high pentrance genes, for example. The information may provide unanticipated therapeutic options, as for the BRCA mutation carriers, but also will yield information regarding risk of potential additional primary tumors (which may be less important in the setting of metastatic disease), as well as enable the identification of at-risk relatives who can use the information to reduce their own cancer risk. This possibility must be recognized so that it is not missed in an effort to simplify the reporting of tumor molecular analyses. The very sensitive next generation sequencing based assays for blood DNA can also identify other sources of mutated DNA. For example, in elegant work from two groups, it has been shown that individuals commonly develop somatic mutations in blood cells with advancing age. Those who accumulate a higher number of such mutations, which appear to increase in frequency and diversity with age, have an increased risk of hematologic disorders. However, the presence of the mutations can complicate the interpretation of germline genetic analyses from blood specimens (25,26). As the examination of the entire exome and genome become progressively more affordable and available, individuals may learn of germline alterations in the absence of typical family cancer histories, but without classic pretest counseling and preparation. We must develop streamlined approaches that provide genetic information in accessible and sensitive ways so that even people without scientific or mathematical backgrounds will have conveniently available and understandable data to help in decision making. Thus, they can benefit from the power of genetic information without being overwhelmed by it. The goal is for them, in partnership with their health care providers, to use it to manage their health and to avoid disease.
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REFERENCES 1. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986;323:643–6. 2. Knudson AG, Jr., Hethcote HW, Brown BW. Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma. Proc Natl Acad Sci U S A 1975;72:5116–20. 3. Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. Fam Cancer 2010;9:449–57. 4. Wells SA, Jr., Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 2010;28:767–72. 5. Elisei R, Schlumberger MJ, Muller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 2013;31:3639–46. 6. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002;346:1459–66. 7. Zhang J, Walsh MF, Wu G, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med 2015;373:2336–46. 8. Schrader KA, Cheng DT, Joseph V, et al. Germline variants in targeted tumor sequencing using matched normal DNA. JAMA Oncol 2016;2:104–11. 9. Schneider KA, DiGianni LM, Patenaude AF, et al. Accuracy of cancer family histories: comparison of two breast cancer syndromes. Genet Test 2004;8:222–8. 10. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015;110:223–62; quiz 263. 11. Lynch PM, Burke CA, Phillips R, et al. An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis. Gut 2016;65:286–95. 12. Vasen HF, Tomlinson I, Castells A. Clinical management of hereditary colorectal cancer syndromes. Nat Rev Gastroenterol Hepatol 2015;12:88–97. 13. Hall MJ, Obeid EI, Schwartz SC, et al. Genetic testing for hereditary cancer predisposition: BRCA1/2, Lynch syndrome, and beyond. Gynecol Oncol 2016;140:565–74. 14. Daly MB, Pilarski R, Axilbund JE, et al. Genetic/familial high-risk assessment: breast and ovarian, Version 2.2015. J Natl Compr Canc Netw 2016;14:153–62. 15. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304:967–75. 16. Cibula D, Zikan M, Dusek L, et al. Oral contraceptives and risk of ovarian and breast cancers in BRCA mutation carriers: a meta-analysis. Expert Rev Anticancer Ther 2011;11:1197–207. 17. Kim H, D’Andrea AD. Regulation of DNA cross-link repair by the Fanconi anemia/ BRCA pathway. Genes Dev 2012;26:1393–408. 18. Howlett NG, Taniguchi T, Olson S, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 2002;297:606–9. 19. Bolton KL, Chenevix-Trench G, Goh C, et al. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 2012;307:382–90. 20. Lord CJ, Ashworth A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat Med 2013;19:1381–8.
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21. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015;373:1697–708. 22. Pritchard CC, Mateo J, Walsh MF et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 2016; Jul 6. [Epub ahead of print] 23. Kamihara J, Rana HQ, Garber JE. Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome. Hum Mutat 2014;35:654–62. 24. Van Allen EM, Wagle N, Levy MA. Clinical analysis and interpretation of cancer genome data. J Clin Oncol 2013;31:1825–33. 25. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014;371:2488–98. 26. Genovese G, Kahler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014;371:2477–87.
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THE GORDON WILSON LECTURE EVOLUTION OF CLINICAL CANCER GENETICS JUDY E. GARBER, MD, MPH BOSTON, MASSACHUSETTS
INTRODUCTION The era of cancer genetics may arguably have begun with the cloning of the first cancer susceptibility gene, Rb1, by Stephen Friend and colleagues in 1986(1), but the existence of a tumor suppressor gene was predicted by Knudson based on modeling of the pediatric tumors, retinoblastoma and Wilms’ tumor(2). He found that some tumors were observed to cluster in families, in which they occurred at younger ages, bilaterally in paired organs, multifocally, and repeatedly from generation to generation. The tumors appeared to be the same histologically and in other observable biological features to the sporadic versions, when they occurred as a single event in a family. As these were pediatric tumors, their rarity enhanced these observations as the tumors occurring without family clustering were also uncommon. Knudson proposed that both the sporadic and familial tumors contained mutations in both copies of a specific gene, but that in the familial case, one copy of the gene was mutated in the germline. The fact that the genes, when not mutated, did not permit tumors to develop led to the expectation that these genes would be “tumor suppressor” genes, so that mutating both copies would permit tumor development. The germline mutation in the tumor suppressor gene would confer increased susceptibility to the specific cancers, but at least one additional event would be necessary to mutate the second copy of the tumor suppressor gene, and often additional mutations would also be needed for tumors to develop. In the 30 years since the cloning of Rb1, cancer genetics has exploded, both the somatically altered genes that drive tumors or are passengers that may still affect tumor behavior and the germline susceptibility genes that have made clinical cancer genetics an essential component Correspondence and reprint requests: Judy E. Garber, MD, MPH, Harvard Medical School, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, Tel: 617-632-5770, E-mail: [email protected]. Potential Conflict of Interest: None disclosed.
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of medical oncology today. In this manuscript, we will review some of the more important developments in cancer genetics that have enabled the development of a new field that continues to evolve for the benefit of cancer patients, and increasingly their unaffected relatives, in order to provide opportunities for cancer prevention and sometimes for targeted therapeutics.
PRINCIPLES OF CANCER GENETICS The primary feature of an inherited cancer syndrome is the clustering of cancers in families. Therefore, a detailed family history is essential to the identification of a syndrome. Families tend to know more about maternal than paternal family members and are often aware of only limited details about the health of their relatives, particularly if there were rare diagnoses or if affected individuals were deceased before the index patient was born. The more distant the relationship, the less reliable the information, and sometimes a diagnosis was just not available in the era before sophisticated imaging and the principle of tissue diagnosis for all malignancies. Nonetheless, the principle of obtaining a 3-generation pedigree often provides very helpful information about a clustering of cancers, or at least will provide guidance as to which family members might have a critical diagnosis to be elucidated by medical records or death certificates. Early age at cancer diagnosis is another essential feature. Therefore, childhood cancers or an adenocarcinoma before age 45 or 50 can be a signal, as can a rare cancer diagnosis. Sarcomas occur in 1 in 100,000 in the population, so the presence of a sarcoma with other early onset disease can be a sign, as can breast cancer in men, or bilateral tumors in paired organs (other than ovarian cancer in which bilateral tumors are common). Clinical acumen may lead to the recognition of a pheochromocytoma because of a family history of sudden death, or death during surgery, rather than a specific history of an adrenal tumor. Once a possible predisposition syndrome is suspected, identification of the individual in the family most likely to carry a predisposing mutation, if one is present, is important. Testing an uninformative family member can misdirect the entire evaluation as a negative molecular evaluation may be over-interpreted as exonerating the entire kindred. Sometimes more than one individual will need to be tested, especially if the syndrome involves clustering of common cancers, so that a “phenocopy” may be present—that is, an individual with the same cancer diagnosis but not the same underlying genetic predisposition, just
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a more common sporadic malignancy that looks like it is part of the familial clustering. In Table 1, the features of hereditary cancer syndromes are enumerated. Individuals who present to their physician or a specialty clinic may elect to undergo germline genetic testing, if it is offered by the genetic counselor or other provider performing the assessment. Generally, a pretest counseling session will inform the patient about the specifics of the cancer syndrome and provide information about the mode of inheritance and some specifics of the genetic test; the kind of information the testing will provide; and the risks, benefits, and limitations of that testing. The goal is for the individual to make an informed decision about whether or not he or she is ready to undergo the testing and to deal with the results, or whether they are not interested in this kind of information or prefer to defer their genetic testing. The passing of the Genetic Information Nondiscrimination Act of 2008 by Congress provides for protection against health insurance discrimination on the basis of genetic information, but not against life or disability insurance discrimination. Individuals must consider the issues that may arise if they are found to carry a predisposing mutation and will need to share that information with other family members, not all of whom may be ready to hear about a potential shared risk. The most difficult implication of genetic testing for people to contemplate is the fact that, if they test positive, each of their offspring and siblings has a 50% chance of sharing that mutation, except for rare circumstances, like mosaicism, where siblings do not share the risk. Most insurers do cover genetic testing for people who meet criteria, usually based on family or personal cancer history, but there can be exceptions. Medicare and other public insurers often have more restrictive coverage. Genetic counselors are indispensable in the provision of pretest information, and perhaps even more important in disclosure of results and subsequent discussion, as patients may need assistance in sharing the essentials TABLE 1 Features of Hereditary Cancer Syndromes • • • • • • • • •
ancer in two or more family members in the same lineage C Early age at cancer diagnosis Multiple primary tumors in same individual Bilateral or multiple rare cancers Constellation of tumors consistent with a hereditary cancer syndrome (e.g., Lynch, Cowden) Multiple affected generations Congenital anomalies or associated benign conditions Specific tumor histologies Findings on tumor genotyping
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of complex information with relatives. However, as genetic testing has become more mainstream, different models are being examined in light of the workforce issues that limit the availability of genetic counselors, so that nurses, physicians, and online materials are taking on portions of their roles. The goal is for individuals to embrace the fact that most cancer genetic testing can either be reassuring (they test negative) or provide information they can use to obtain the proper care. Such care may often help them to avoid a cancer diagnosis or at least have early diagnosis when cure is more likely. Anxiety is often an issue, but in many studies, early sadness and anxiety is replaced by empowerment for most people. However, many still struggle with the repeated screening studies and challenges of having family members deal with testing, care, or cancers.
MEN2 Most, but not all, inherited cancer susceptibility syndromes occur because of mutations in tumor suppressor genes. However, syndromes have been identified in which the predisposing gene is an oncogene, inherited in the activated form, and a typical second hit is not necessary. The prototypical example is Multiple Endocrine Neoplasia Type 2 (MEN2), which is attributable to germline mutations in the RET proto-oncogene. There is interesting genotype–phenotype correlation in this gene, with clustering of specific activating mutations by functional region of the gene associated with full MEN2A, or familial medullary thyroid carcinoma only, or MEN2B, or finally, conversely, inactivating mutations associated with Hirschsprung’s disease. The latter is not a cancer predisposition syndrome at all but rather a syndrome of the congenital absence of ganglion cells from the colon(3). Testing for germline mutations in RET is the standard of care for all cases of medullary thyroid cancer, which could be the first recognized member of the cluster of diagnoses comprising MEN2, or could be a manifestation of the more limited familial medullary thyroid cancer. The importance of screening for germline RET mutations is emphasized by the recommendations for management of mutation carriers, for whom recommendations are to undergo prophylactic thyroidectomy before age 6, because of the very early age at which medullary thyroid cancers have been observed in mutation carriers. Mutation carriers are also screened annually with biochemical screens for pheochromocytoma and hyperparathyroidism. Therefore, genetic testing is recommended for adults and children at or before age 5(3). In addition, it is
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now possible to treat advanced medullary thyroid cancer with protein kinase inhibitors, including Vandetanib(4) and Cabozantinib(5), which inhibit RET activity.
GENETIC HETEROGENEITY Genetic heterogeneity is defined as the phenomenon in which a single phenotype or genetic disorder may be caused by a germline mutation in any of a number of genes. Genetic heterogeneity is commonly observed in cancer genetics. A remarkable example of genetic heterogeneity is observed in pheochromocytomas. The rare tumor type can occur as a single or the first manifestation of inherited endocrine cancer syndromes attributable to germline mutations in RET, as part of MEN2A, in VHL as part of von Hippel Lindau syndrome, and in the SDH complex genes (SDHA, B, C, D, and TMEM127), which code subunits of the mitochondrial complex II. In one series, 25% of individuals with pheochromocytomas collected without regard to family history were found to carry a mutated germline allele in one of the above genes, and that was before all of the SDH genes had been identified(6). In general, about 5 to 10% of tumors are ultimately attributable to a germline predisposing mutation, so the rate of germline mutations among individuals with pheochromocytomas is higher than anticipated and has not yet been duplicated. Pheochromocytomas provide examples of another phenomenon in cancer genetics. Rare tumors and syndromes have often provided a clue to the presence of an inherited predisposition. Childhood cancers are uncommon, partly because children have generally not lived long enough to have been sufficiently exposed to carcinogens that could contribute to tumor development. Recently, large series have identified germline mutations in recognized predisposition genes in only about 10%(7), which is comparable to the prevalence in adult cancer patients as well(8). Other possible explanations for elevated rates of pathogenic germline mutations in series include: (1) erroneous interpretation of sequence variants to include alterations whose functional significance is not clearly deleterious, (2) misclassification of tumor diagnoses, and (3) enrichment of unselected series with cases whose family histories were incompletely ascertained. This can be a particular challenge as many individuals are unaware of the specifics of cancer diagnoses, particularly if a tumor is a rare type, if the affected relative is somewhat distant, or if the parent connected to the branch of the kindred affected with the cancers is deceased(9).
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HEREDITARY COLORECTAL CANCER SYNDROMES Common cancers can also be featured in hereditary cancer predisposition syndromes. Colorectal cancers are components of some of the best known, best characterized but ironically least often recognized syndromes. Approximately 10 to 30% of colorectal cancers are considered familial, or not sporadic. Please refer to a useful comprehensive review(10). Nearly 1% of colon cancers are attributable to Familial Adenomatous Polyposis (FAP) associated with mutations in the tumor suppressor APC gene, as well as one of the few recessive syndromes, MutYH gene mutations, in which the syndrome is termed “MYH-associated polyposis,” or MAP (and requires the affected individuals to have inherited mutations in both copies of MutYH). The rate of new or de novo mutations in APC is 20%, of which about 20% are mosaic. However, once an individual has a mutation, even if de novo (so their siblings may not be at risk), she or he can pass it to offspring. Approximately 95% of individuals will have a molecular diagnosis in the era of analysis of APC by next generation sequencing and analysis of rearrangements by deletions and duplications (Del-Dup), plus MutYH examination. The syndrome includes the classic syndrome of carpets of polyps in the colon, presenting from the teens throughout life, and associated with a nearly 100% risk of colon cancer by age 50. Adenomas can be found in the duodenum and in the small bowel. Other tumors also occur excessively in FAP, including thyroid adenocarcinomas and desmoid tumors. Much of the genetic testing is done in childhood and adolescence, since management of the syndrome can include prophylactic colectomy at young ages. Chemopreventive interventions with NSAIDs and DFMO (difluoromethylornithine) have been examined in several large clinical trials and, while active, have not achieved standard of care status(11). Inherited GI Cancer Syndromes and their Susceptibility Genes Syndrome
Gene(s)
FAP Lynch syndrome Peutz-Jegher syndrome Juvenile polyposis syndrome Cowden syndrome “Proofreading” or hypermutable polyposis
APC, MutYH (recessive) MLH1, MSH2, MSH6, PMS1, PMS2, EpCAM STK11 SMAD, BMPR1A PTEN POLD1, POLE
The most common hereditary GI cancer predisposition syndrome is Lynch syndrome, named for Henry Lynch, one of the giants of cancer
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genetics who first recognized it and whose carefully documented collection of families and specimens enabled the identification of multiple genes conferring predisposition. The “mismatch repair” genes includes MLH1, MSH2, MSH6, and PMS2, which are the “spellcheck” genes repairing small DNA errors, and EpCAM, an unusual gene that is responsible for methylation as a means of inactivation of DNA repair. When these genes are inactivated, the DNA repair leads to a stuttering pattern of erroneous DNA in the resulting tumor tissue called “microsatellite instability (MSI)” which can be detected in a molecular pathology laboratory. Therefore, tumors can be tested to see whether they manifest MSI, and current College of American Pathologists guidelines require that all colorectal and endometrial tumors be tested either for MSI or for inactivation of the proteins made from the genes enumerated above using immunohistochemistry. Although MSI is a hallmark feature associated with Lynch syndrome, approximately 15% of sporadic colorectal cancers have the MSI-high phenotype because of somatic MLH1 promoter hypermethylation, which also can underlie the loss of MLH1 (often with loss of PMS2) in tumors negative for MLH1 by IHC. Testing tumor DNA for the somatic BRAF mutation V600E is routine when MLH1 protein expression is absent, as it correlates with sporadic tumor rather than Lynch syndrome. If none of the alternative mechanisms is suggested by this analysis, then individuals whose tumors manifest MSI or specific protein absence by IHC should be referred for germline genetic testing for Lynch syndrome(10). Lynch syndrome is a relatively common cancer predisposition syndrome, and it is estimated that up to 500,000 carriers exist in the United States, though many are unaware of their status. This is unfortunate, as they have very high lifetime colorectal and endometrial cancer risks, and these cancers can be prevented with early and frequent colonoscopy and prophylactic hysterectomy. Lynch patients do not develop carpets of polyps like FAP, but do develop their adenomatous polyps at an accelerated pace. A colonoscopy every 1 to 2 years is recommended beginning at age 25, and upper endoscopy is added at intervals(12). Because the risk of endometrial cancer is also increased, prophylactic hysterectomy is recommended, as pelvic ultrasound and endometrial biopsies are diagnostic rather than screening procedures and have not been shown to be sufficient to diagnose early disease. The ovaries may also be removed though the risk is not as high as in other syndromes, but effective screening strategies for ovarian cancer do not yet exist. Patients diagnosed with colon or endometrial cancers may have a curable disease, and learning that they have Lynch syndrome through tumor and germline testing can help make sure they do not
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develop additional primary tumors. Relatives should be tested to learn whether they share the altered gene and the associated cancer risks, or do not share the mutation and do not require all of the care(13).
HEREDITARY BREAST-OVARIAN CANCER SYNDROME The clustering of breast cancer in families has long been recognized. The modern era arrived with the mapping of the first breast cancer susceptibility gene, BRCA1, by Mary Claire King and colleagues in 1990. By 1994, BRCA1 had been cloned, and BRCA2 was mapped and cloned shortly thereafter. By 2015, hundreds of thousands of individuals had undergone genetic testing for germline mutations in BRCA1/2, and thousands had contributed data and specimens to research in large consortia, which has enabled more rapid and thorough study of the genetics of hereditary breast-ovarian cancer. The recognition of the prominence of ovarian cancer helped to distinguish the BRCA1/2 families early on, and current data show that mutations in these genes also confer increased risk of male breast cancer, pancreatic cancer, prostate cancer, melanoma, and possibly gastric and other tumors as well. Multiple international screening studies have demonstrated the superior sensitivity of breast MRI to mammograms. Evidence-based guidelines(14) provide recommendations for initiation of breast surveillance with MRI alone at age 25, with the addition of mammograms at age 30, with alternating imaging every 6 months. There is no effective ovarian surveillance at this time, though active research is ongoing. The most important intervention is risk-reducing bilateral salpingo-oophorectomies (RRSO), which is recommended after completion of childbearing at about age 35 to 40. The lifetime ovarian cancer risk is 40-to 60% in BRCA1 and 15 to 20% in BRCA2, with population risk in the range of 1.3%. RRSO has been shown to reduce the risk of ovarian cancer by more than 90%, and to reduce breast cancer risk as well. Moreover, RRSO has been shown to reduce both ovarian and breast cancer mortality in carriers(15). Bilateral mastectomies are discussed as an option for carriers, with recognition that a decision to proceed to surgery is a very individual one. However, the rates of mastectomies have been rising as reconstruction options have improved, with the more frequent use of nipple-sparing and autologous tissue procedures, as well as novel approaches to implant reconstruction. Hormone replacement has been shown to be safe after RRSO, even in women who retain their breasts, though the data are not ideal. Oral contraceptives have
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been shown to reduce or delay ovarian cancer risk in both BRCA1 and BRCA2 carriers, with no effect on breast cancer risk in BRCA1 carriers, and a small increase in BRCA2 carriers(16). The BRCA1 and BRCA2 genes have been shown to have multiple and critical roles in DNA repair. Clearly, carriers of a single mutation have basically normal physiology and are able to reproduce, but their tumors are known to have generally lost the second copy of the involved gene and then to have significant defects in DNA repair. The defects include problems with the repair of double strand breaks in particular. Recognition of the mechanism of action of these genes led to the observation that first BRCA2 and later BRCA1 could occur in rare individuals as compound heterozygous mutations—that is, an individual with both copies of the gene containing a mutation in the germline. The clinical manifestation was a form of Fanconi anemia, and the recognition of this link by D’Andrea and colleagues permitted the evaluation of the multiple other genes identified in the Fanconi anemia pathway of DNA repair, all of which have been shown to confer increased risk of breast or other cancers, though often with more moderate risk, when present as a heterozygous mutation (17,18). It is now possible to test for germline mutations in these genes as well as BRCA1/2, enabling identification of the underlying mutations in families in whom BRCA1/2 testing was negative, despite the presence of the clinical features suggesting the presence of an underlying predisposition. The other important result of the understanding of the role of BRCA1/2 and related genes in DNA repair has been the development of therapies that target the associated deficiencies. For example, the platinum salts, cis- and carboplatin (though not all platinum compounds), are known to create DNA-cross links that require intact double strand break repair to excise(19). Because BRCA1/2 tumor cells lack intact double strand break repair, the tumor cells in which both copies of the BRCA1 or BRCA2 genes are absent have been shown to often be more vulnerable to killing by the platinum salts. Examples include triple negative breast cancer in BRCA carriers and ovarian cancer, for which carboplatin is a backbone of treatment. In ovarian cancer, for example, individuals who carry a BRCA2 mutation have a superior survival, perhaps mediated by the enhanced response to platinum therapy(20). In addition, the PARP inhibitors, novel therapies targeting a specific DNA repair protein, PARP1, are in development. At this time, a single PARP inhibitor is approved for treatment of women with a germline BRCA1/2 mutation who have recurrent ovarian cancer. These drugs are in clinical trials in women with mutations and recurrent breast
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cancer, as well as in a large international adjuvant therapy clinical trials in women with a germline BRCA mutation in breast cancer at time of diagnosis. The drugs are in trials in combination with immunotherapies and other agents, and also beyond breast and ovarian cancer. For example, in a trial in men with metastatic castrate resistant prostate cancer, response to PARP inhibitor was predicted by germline or somatic mutation in the BRCA1/2 genes or associated DNA repair genes(21). Recent work identified an 11% prevalence of germline BRCA2 and related DNA repair genes in men with diagnosis of this aggressive tumor(22). Trials are also in progress in the treatment of pancreatic cancer among BRCA1/2 carriers.
LI FRAUMENI SYNDROME In 1969, Li and Fraumeni published their landmark paper in which they questioned whether a clustering of a diverse group of tumors in a single family could be the result of a single predisposing mutation. Most cancer predisposition syndromes at that time featured predominantly a single cancer. Of course, eventually most predisposition syndromes have been shown to include more than one tumor type, but Li Fraumeni is still notable for the extent of diversity of early onset cancers, with excessive incidence of sarcomas, adrenal cortical carcinomas, breast cancers, brain tumors, and very early onset of a spectrum of adenocarcinomas. Germline mutations in the TP53 gene have been shown to account for the great majority of classic Li Fraumeni families, at least 70%. Families can be devastated by this syndrome, with cancer deaths among children and young adults occurring excessively, and multiple primary tumors particularly common in individuals with Li Fraumeni syndrome. Data suggesting enhanced carcinogenic effects of therapeutic radiation among carriers have led to recommendations to avoid therapeutic radiation in carriers to the extent possible. Recent data have raised the question of whether there could be a broader spectrum of Li Fraumeni syndrome, including some with less penetrant forms, such as individuals whose TP53 mutation was found on expanded genetic testing which looks at a panel of 20 or more susceptibility genes rather than a single gene at a time. Many of these individuals appear to have cancer histories that are not as dramatic as some of the patients whose family configurations have led to targeted TP53 mutation testing. This is currently under study. A recent review provides detailed information about LFS(23).
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NEW CHALLENGES AND OPPORTUNITIES As technologies advance, new capacities introduce new challenges. For example, many novel therapeutic strategies target specific somatic mutations in particular genes in tumors. Therefore, it is becoming the standard of care to biopsy tumors to document metastatic disease and to characterize the mutation spectrum to look for therapeutic targets(24). Examination of the germline DNA in that setting may take place primarily to “subtract out” those mutations and leave the acquired somatic “driver” mutations. However, results of the testing may identify mutations that should be examined in the germline when they involve BRCA1 or other DNA repair genes, or Lynch syndrome or other high pentrance genes, for example. The information may provide unanticipated therapeutic options, as for the BRCA mutation carriers, but also will yield information regarding risk of potential additional primary tumors (which may be less important in the setting of metastatic disease), as well as enable the identification of at-risk relatives who can use the information to reduce their own cancer risk. This possibility must be recognized so that it is not missed in an effort to simplify the reporting of tumor molecular analyses. The very sensitive next generation sequencing based assays for blood DNA can also identify other sources of mutated DNA. For example, in elegant work from two groups, it has been shown that individuals commonly develop somatic mutations in blood cells with advancing age. Those who accumulate a higher number of such mutations, which appear to increase in frequency and diversity with age, have an increased risk of hematologic disorders. However, the presence of the mutations can complicate the interpretation of germline genetic analyses from blood specimens (25,26). As the examination of the entire exome and genome become progressively more affordable and available, individuals may learn of germline alterations in the absence of typical family cancer histories, but without classic pretest counseling and preparation. We must develop streamlined approaches that provide genetic information in accessible and sensitive ways so that even people without scientific or mathematical backgrounds will have conveniently available and understandable data to help in decision making. Thus, they can benefit from the power of genetic information without being overwhelmed by it. The goal is for them, in partnership with their health care providers, to use it to manage their health and to avoid disease.
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