Genetic basis of cancer Katherine W. Klinger Integrated Genetics, Framingham, Massachusetts, USA Tumorigenesis is a heterogeneous process that occurs over a relatively long time span, progressing from a single cell through intermediate stages to give rise to a tumor that becomes more aggressive over time. Recent discoveries have begun to define the molecular events that underlie this progression in breast and colon cancer. Current Opinion in Biotechnology 1991, 2:812-817

Introduction The progression from a normal cell to a tumor is believed to result from a series o f acquired genetic changes. According to the multi-hit theory, the first mutation or 'hit' is predisposing; subsequent hits occur over time [1,2o]. This is demonstrated by autosomal dominant cancer pedigrees in which there is germ line inhei'itance of a recessive mutant allele, with subsequent neoplasia due to somatic loss of the normal allele [3]. Common cancers exhibit a wide range o f phenotypic heterogeneity. Because tumorigenesis requires the accumulation of a number of genetic changes, individual phenotypes will depend on which altered loci have accumulated, the nature of the mutation at each locus, and perhaps the order in which these changes occurred. Non-genetic factors such as diet or onset o f puberty can also contribute to heterogeneity. Two tools have been used to dissect these complex events. The first method uses analysis of tumor tissue for activation o f oncogenes or loss of heterozygosity (LOH) in a direct search for loci involved in sporadic forms of cancer. LOH studies analyze constitutive and tumor tissue for a variety of chromosomally mapped, highly polymorphic markers. Chromosomal loci showing consistent LOH in a particular tumor-type are candidates for involvement in tumorigenesis, often as the site of tumor suppressor genes. The second method used to unravel the complex events involved in tumorigenesis is family studies. Many cancers occur in two forms: a rare familial form, and a more c o m m o n sporadic form. In family studies it is presumed that loci important to the development of disease will also be causative agents in sporadic tumors.

Colon c a n c e r Most colon cancer is sporadic, but there is an inherited susceptibility to colon cancer with an increased risk of adenoma and carcinoma of the colon in rela~,es of colon carcinoma probands. It has been suggested that there is a

predisposition to polyp formation, resulting from a dominant, partially penetrant, gene. Carcinogenesis would result from subsequent genetic changes and environmental factors. Research into colon cancer has benefitted from both a familial model o f tumorigenesis, familial adenopolyposis coli (FAP), and ready access to an intermediate stage of tumor formation. Most colon cancer arises from adenomatous polyps that can b e used to monitor somatic changes. FAP is inherited as a highly penetrant autosomal dominant with incidence ranging from 1 in 7000 to 1 in 30 000. IJnkage of FAP to the long arm of chromosome 5 (5q) was first demonstrated by Bodmer et at [4]. LOH of 5q is also found in 20--60% of sporadic colon tumors [5,6], suggesting that the same locus is involved in FAP and sporadic colon cancer. In premalignant colon tumors, the I.OH of chromosome 5 is about 25% [7,8o], implying that alterations o f FAP may be an early event in the development of colon cancer. Interestingly, there is no increased LOH of 5q in the polyps of FAP. Thus, one copy of the mutant allele must be sufficient to trigger polyp formation. Genetic changes are c o m m o n in colon cancer [4,9--13]. The molecular events accompanying the progression from normal cell to tumor (see Fig. 1) have been established by a combination o f family and I.OH studies. Although shown as a progression, it is important to note that the number of changes accumulated is more important than the order in which they accumulate. There is a high degree of LOH for both chromosomes 17 and 18 [11,12]. Deletions of the short arm of chromosome 17 (17p; which contains the P53 gene) occur in more than 75% of colon cancer, often as late events associated with a switch from the benign adenomatous state to the malignant state [14]. In more than 50% o f colon cancer p53 is mutant. The wide range of mutant p53 activities identified in colon tumors may contribute to disease heterogeneity. Some p53 mutations abolish tumor suppressor function, whereas others confer oncogenic activity [15,16]. Wdd-type p53 protein has no transformation potential, and is generally dominant to mutant or oncogenic

Abbreviations ESR---estrogen receptor; FAt'---familial adenopolyposiscoil; LOH---loss of heterozygosity. 812

(~) Current Biology Lid ISSN 0958-1669

Genetic basis of cancer Klinger

p53. Some mutant forms of p53, however, can inactivate wild-type p53 through sequestration of wild-type p53 into oligomers with mutant p53 (a functional, rather than genetic, inactivation of the normal allele). Often associated with large adenomas, about 50% of tumors show a common deleted region on chromosome 18 that contains the gene DCC(deleted in colon cancer) [8o,15]. Somatic mutations of the k-ras proto-oncogene occur in up to 60% of sporadic colon adenomas, 50% of carcinomas, but ordy 7% of adenomas in FAF patients [8°]. Additional chromosomal changes are also found In colon tumors and, on average, most colon carcinomas show allele loss on four to five chromosome arms. Genes on these chromosomes may include other tumor suppressor genes, or impact heterogeneity. It is also possible that some mutations in tumors are epiphenomena, unrelated to tumor function. Recently, two important genes related to colon cancer have been cloned from the region 5q21. The first, MCC (mutated in colon cancer) encodes a protein of approximately 829 amino acids that has the potential to form coiled-coils [17°]. At least 15% of colorectal cancers bear mutations (point mutations or gross structural changes) of MCC No germ line mutations of MCChave been found in YAP patients [18..] and it is located 50kb outside the region deleted in an FAP patient Thus MCC is not the gene responsible for FAP, and probably plays a role later in the pathway of tumorigenesis. The gene responsible for FAP, called APC or DP2.5, was simultaneously cloned by two groups in the past year [18°.-21 o.]." Positionally, A_PCis very close to MC~ but it is transcriptionally oriented in the opposite direction. It encodes an 8.5-9.5 kb transcript, whose sequence predicts a protein that is hydrophilic and cytoplasmic, and that has coiledcoil potential, like the MCC protein. It is possible that MCC and APC form homo- or heteroduplexes, and may be part of the same biochemical pathway or complex. A variety of germ line mutations of APC have been identified in FAP patients that were not present in unaffected members of FAP pedigrees. Mutations In APGwere also found in sporadic colorectal cancers. Thus, one or more genes in 5(121 probably contributes to colorectal cancer formation. To date, approximately 80 % of the tumors examined have been heterozygous for point mutations in APC or MCC This is consistent with reports of chromosome 5q

deletion (i.e. allelic loss) in only 20-40% of sporadic colorectal cancer. Interestingly, a mutation in APC has been found that creates an altemam'e splice site [21oo], which generates a new 303 bp exon in the gene. Both splice sites are used to generate transcripts, with the larger product more abundant than the smaller product. Thus, as in the case of p53, at least some mutations in APC and MCC must act in a dominant manner. It has been proposed that such dominance could arise from incorporation of mutant gene products into multimers, inactivating the wild-type protein [22]. Given that four APC mutations are nonsense or frame-shift mutations, this seems an uniikely explanation [20°°]. Bodmer's suggestion of a growth suppressor threshold effect seems more plausible [4]. In this model, hemizygosity of the mutant allele is sufficient to yield random fluctuations in the level of gene product. When the level falls below a critical threshold, adenomatous growth can occur. It has also been proposed that there may be a different microenvironment in FAP that facilitates polyp formation [23]. In FAP, a cell hemizygous for a germ line mutation resulting in low levels of gene product is surrounded by hemizygous tissue. In sporadic cancer, however, such a cell is surrounded by normal tissue that might work to suppress tumor formation until other genetic alterations occur. The current working hypothesis [8.,18..,21..,24] is that APC is directly involved in the induction of widespread epithelial hyperprolfferation. Germ line mutations give rise to adenomatous polyposis, whereas somatic mutations are an early step in the pathway from normal mucosa to sporadic adenoma. APC has a rate-limiting function in the development of adenoma. If a single allele is inactivated, the decrease in normal gene expression may lead to inetficient control of cell proliferation. Mutation or loss of both alleles magnifies the proliferative effect, but is n o t required. Different alleles at the locus could give rise to various colorectal cancer 'phenotypes'. If the MCC and APC proteins operate in the same biochemical pathwa)(s), this could explain some of the phenotypic variation seen in FAP kindreds. As a co-segregating gene, MCC could influence the effect of an inherited APC mutation. Additional genetic loci seem to act as'second events' in later stages in tumor progression, after formation of the polyp. Thus, mutations of P53, and DCC are common in colorectal cancer, but are less frequently

MCC mutatiom

I mutations APC



Ras activation

Chro 18 loss.e,I (DCC gene) I

Ch. .e, I 17 loss (p53 gene) I


chromosone oss 2


colon cell


cell growth

denoma I

Adenoma II

Adenoma III



Fig. I. The proposed pathway to neoplasia. Tumor formation in colorectal cancer results from a number of genetic changes. Some of the causative genes have now been cloned and identified. (Modified and updated from [51]).



Mammalian gene studies

seen in adenomas, whereas the k-ras mutation is associated with large adenomas. These 'second events' can be heterogenous, with different genetic changes mediating transition to cancer in different adenomas. Loss of other chromosomes may contribute to tumor heterogeneity.

Breast cancer

Like colon cancer, breast cancer is a heterogeneous entity that involves genetic changes at multiple loci, as well as probable environmental factors. The complex nature of breast cancer can be seen in the diverse biological characteristics of the tumors. Studies of gene amplification and LOH are complicated by both the nature of the tumor, and the nature of the biopsy. The ratio of normal to cancer cells in a given biopsy is variable, depending on the amount of stroma present and the degree to which lymphocytes have infiltrated the tumor. The two alleles contributed by the normal cells can act to falsify obscure LOH ff a large number of normal cells are present in the biopsy tissue. Conversely, many tumors are polyploid, leading to false estimates of gene amplification. With those caveats, however, recent progress has been made in proposing a 'pathway to tumorigenesis' for breast cancer (Fig. 2) that is si/~ilur to the one constructed for colon cancer [25]. As with colon cancer, the order in which genetic changes occur is less important than the total number of changes that accumulate. Activation of c-myc is found in 16-56% of primary tumors, with amplification present more often than rearrangements [26,27]. A significant correlation was found between c-myc amplification and poor prognosis in pa-

tients [27]. The neu oncogene (also known as c-erb-b2 or her-2) is commonly amplified in breast tumors, and plays a role in the neoplastic progression of the disease, perhaps at an early step in the pathway [27-34]. Both male and female transgenic mice canting a mutant n e u oncogene uniformly developed breast cancer [35]. Slamon and colleagues [28] originally reported that amplification of the new oncogene was correlated with positive lymph nodes, shorter time to relapse, and lower survival in women with breast cancer, and this could be used to predict clinical outcome. The prognostic value of this marker (particularly in node negative breast cancer) remains unsettled [28~1,36~7]. The estrogen receptor (ESR) is present on about 70% of rumors from post-menopausal patients, but is less common (30%) on tumors derived from pre-menopausal patients. In general, ESR positive tumors respond to hormonal treatment, and are correlated with good prognosis. About 20-30% of receptor posi~'e tumors, however, are resistant to hormone therapy, and some initially responsive tumors grow resistant over time [38]. This resistance could arise from mutations that inactivate ESR, or possibly by estrogen stimulation of factors acting as growth promoters (e.g. neu) enhancing metastatic potential [39]. The ESR gene may be linked to breast cancer in late-onset familial disease [40]. The expression of the tumor suppressor gene NM23 appears to be correlated with progression to metastasis [41,42]. Expression of NM23 is decreased in breast tumors with lymph node metastases, whereas adenomas and carcinomas from node-negative patients have higher levels of expression. Expression of NM23 was associated with longer disease-free survival, lack of lymph node metastasis, and good prognosis in studies by Hermessy

Cells of Ducatal Epithelium

p53 myc int2 nm23


) Invasion

) Metastasis

Fi8. 2. Possible events in the development of three forms of breast cancer. The mutations that occur at each stage are noted on the figure. (Adapted from the presentation described in [25].)

Genetic basis of cancer Klinger 8"15 et aL [42]. It has been p r o p o s e d that the NM23 gene product acts to suppress the metastatic phenotype. Family history is, in fact, the most powerful factor contributing to breast cancer risk. Close relatives o f probands have an increased risk of breast cancer, although most cases in the general population are sporadic, presumably the result of somatic events. Mapping familial breast cancer may allow the identification of loci that are also important to the development of sporadic breast cancer. As always, family studies are impacted by the heterogeneity of cancer. Multiple cases can occur in families without inherited susceptibility, families with inherited susceptibility can also have sporadic cases of breast cancer, and the disease is not fully penetrant, depending on age, gender, and non-genetic factors for expression. Two important studies of familial cancer recendy implicated predisposing tumor suppressor genes. H-Fraumeni syndrome is a rare, dominantly inherited, multi-organ cancer syndrome, in which the susceptibility to the onset of malignant tumors at an early age is increased, especially in breast cancer. Affected individuals inherit a germ line mutation of p53 in both tumor and normal cells [43"]. This mutation is the 'first hit', conferring susceptibility; subsequent somatic loss of the wild-type allele is the 'second hit'. Although the germ line mutation is predisposing, the risk of tumor formation in different organs is variable. Mutation of p 5 3 may be a critical rate.limiting step for breast tumor formation. In less common tumor types seen in Li-Fraumeni syndrome, the germ line p 5 3 mutation may only contribute to tumorigenesis with other, less frequent genetic changes forming the rate-limiting step. Further, the fact that only one or a few tumor types occur per susceptible individual implies either that additional mutations are needed for tumor formation, or that in the spectrum of p53 mutations, only weakly transforming mutations can be carried as germ line mutations. Allelic loss at 17p is often seen in breast tumors [44]. Point mutations in p53 have been found in sporadic breast tumors, and there is evidence f o r p 5 3 over-expression in 45% of breast tumors [45]. Frequency of allelic loss does not correlate well with the high incidence of p 5 3 mutations in breast cancer, unless, as with colorectal cancer, o n e postulates that at one-half gene dosage p 5 3 levels occasionally drop below a critical threshold [46]. Alternatively, a tran.~acting regulator at another locus could explain this phenomenon. LOH studies of breast tumors imply that there may be a second tumor suppressor locus on 17p, distal to p53 [44,47]. In fact, LOH studies show consistent losses of 17p, 17q, 16q, 13q, l l p and l q in sporadic breast tumors [44,47]. Recently, linkage was found between breast cancer in families showing susceptibility to early onset disease and polymorphic markers on 17q21 [48°]. The disease gene was modelled as an autosomal dominant with a major effect on risk of breast cancer. Linkage analysis showed that families with inherited susceptibility to breast cancer form at least two groups: one with late-onset which is unlinked to polymorphic markers on 17q, and one with early-onset of disease linked to the anonymous DNA

marker D17S74. The region 17q21 contains a number of loci implicated as having a role in breast tumorigenesis. These include the neu oncogene, the tumor suppressor gene NM23, estradiol-17 ~3-dehydroxylase, H o x 2, the cxretinoic acid receptor, and the wnt3 locus. Interestingly, the majority of tumors with LOH of 17q show amplification of n e u [49]. Alternatively, a yet to b e discovered gene could b e the causative factor. Thus, for breast cancer, as was the case with FAP and colon cancer years ago, a chromosomal region has now been identified that appears to play a role in tumor formation. Further studies are underway to identify the causative gene for early onset disease, its normal function, and what alterations lead to inherited susceptibility. Family studies of tumorigenesis in colon cancer were aided by the presence of a reliable marker of susceptibility, polyp formation. Although the results are preliminary, it appears that benign proliferative disease may serve as a similar marker for breast cancer


Conclusion It is clear that a complete understanding of the genetics of c o m m o n cancers is not yet possible. A c o m m o n theme, however, has emerged in which tumor formation, invasion and metastasis are the consequences of genetic alteration at multiple loci, including both oncogenes and tumor suppressor genes. In the past year there has been considerable progress in elucidating the nature and role of some determinants o f tumor formation. A better understanding of molecular carcinogenesis should lead to early diagnosis and perhaps new therapeutic options, for breast and colon cancer.

References and recommended reading Papers of special interest, published ~thin the annual period of review, hm~ been highlighted as: • of interest •• of outstanding interest 1. KNtmSONAG: MUTKrIONANDCANCER;STATISTICALSTUDYOF Rvr~OBLmrOMAProc Naa Acad $ci USA 1971, 68:820--823. 2. HABERDA, HOUSM*NDE: Rate.limiting Steps: the Generics • of Pediatric Cancers. Cell 1991, 64:5--8. This paper presents a reviewof target theory and the multi-hith)~)othesis. 3. DEMARsR: 23rd Annual S#~Oosium Fundamental Cancer Research. Williams & Williams: Baltimore, 1976, pp 105-106. 4. BODMERWF, BAIIx-'YCJ, BODMERJ, BUSSEYHJR, El.US A, GO~',IAN P, PUERBELLOFC, MURDAYUA, RIDERSH, S~.M~BLERP,



ET At.: Localization of the Gene for Familial Adenomatous Polyposis on Chromosome 5. Nature 1987, 328:614-616. ASHTON-PdCKAROT PG, DO,',,'IAPMG, NAK&MURAY, MORRISRG, PURDIECA. STEEl-CM, EVANStlJ, BIRDCC, ~ All: High Frequency of AF~ Loss in Sporadic Colorectal Carcinoma due to Breaks Clustered in 5q21-q22. Oncogene 1989, 4:1169-1174. WYLLmAH, AStrrON-RICKAR~rP, DUNLOPMG, NAKAMURAY, PmO J, PURDEC, SrF.ALECM, Bran CC: Status of the APC


Mammalian gene studies Gene in Familial and Sporadic Colorectal Tumors as Determined by Closely Flanking Markers. in Hereditary Colorectal Cancer edited by Utsunomb'a J, Lynch HT [book]. New York: Springer-Verlag, 1990. 7.

VOGEISIXINB, FEARONER, KERN SE, HAM]].TONSR, PRE1SLNGER AC, NAKAMURAY, WHITE R: AIlotype of Colorectal Carcinomas. N EngI J Med 1989, 319:525--532.

8. BtSHOPDT, THOMAS H: Genetics of Colon Cancer. Cancer , Surveys 1990, 9:585-604. The authors present a thorough review of the genetics, epidemiology and molecular genetics of colon cancer up to, but not including, the recent papers on MCCand APC 9.



Cloning and identification of the gene responsible for FAP, contemporaneous with [19,o]. 21. ,°

JOSLYNG, CAm.SON M, THI/VEmS A, ALBERTSENH, GELBERT L, S&MowrrzW, GRODENJ, STEVEt~ J, SPImo k ROBEmSON M, AL: Identification of Deletion Mutations and Three New Genes at the Familial Polyposis Locus. Cell 1991, 66:601-613. Identification of genes within the FAP locus, and characterization of mumoons that play a role either singly or in concert, in colorectal cancer. See also [18*%19**]. 22.

BOURNE H: Consider 351:188--190.






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KINGM-C: Genetics of Human Breast Cancer. Am J Hum Genet 1991, 49A127.


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MONPEZATJ, DEIATi'RE O, BERNARDA, GRUNWALDD, REMV1KOS Y, MULER1SM, SOALMONRJ, FRELATG, DtrIRa2AUXB, THOMASG: loss of Alleles on Chromosome 17 in Polypoid Colorectal Carcinomas. I n t J Cancer 1988, 41:404-408.


VAmEYJM, SWALLOWJE, BRAMMARWJ, WHrFI'AKERJL, WALKER RA: Alterations to Either c-erbB-2 (neu) or c-myc Protooncogenes in Breast Carcinomas Correlate with Poor Short-term Prognosis. ~ 1987, 1:423-430.


FEAgON ER, CHO KIL NIGRO JM, KERN SE, S~,ONS JW, RAPPORTJM, HAMILTONSR, PREISINGERAC, THOMASG, KINZLER KW, VOGEtSTELN B: Identification of a Chromosome 18¢1 Gene that is Altered in Colorectal Cancers. Sc~,nc~ 1990, 247:49-56.


SIAMONDJ, CLARKGM, WONG SG, LEVINWJ, UmEH A, McGUIRE WL: Human Breast Cance~ Correlation of Relapse and Survival with Amplification of the HER-2/neu Oncogene. Science 1987, 235:177-182.



BAKERSJ, FEARON ER, NIGRO JM, HAMILTON SR, PREISLNGER AC, JESSUP JM, VAN "IXahXN P, LEDB~rJJ.R DH, BARKERDF, NAKAMURAY, WHrlE R, VOGELSTEINB: Chromosome 17 Deletion and p53 Gene Mutations In Colon Cancer.. Sc/ence 1989, 244:217-221.

VAN DE VrJVERMJ, PETERSEJL, MOOI WJ, WISMANP, LOMA.~r3J, DALESIO O, NUSSE R: Neu-Protein Overexpression in Breast Cancer. N Engl J Med 1988, 319:1239-1245.


At] IU, CAMPBELLG, LIDEREAUR, CALLAHANR: Lack of Evidence for the Prognostic Significance of c-erbB-2 Amplification In Human Breast Carcinoma. Oncogene Res 1988, 3:139-146.


~ S, JANGSK: Presence of a Potent Acth'ating Sequence in the p53 Protein. Science 1990, 249:1046-1049.



RAYCROFTL, WU HONGYUN, LOZANO G: Transcriptional Activation by Wild-type but Not Transforming Mutants of 1)53 Anti-oncogene. Sc~-~ce 1990, 249:1049--1051.

SLAMONDJ, GODOLPHLNW, JONE LA, HOLTJA, WONG SG, KEITH DE, IEVINWJ, STUAIrrSG, UDOVEJ, ULRICHA, PRESSMF: Studies of the HER-2/neu Proto-Oncogene In Human Breast and Ovarian Cancer. Sc/ence 1989, 244:707-712.


KL'E~R K, NmBERT M, VOGEtSTELN B, BRYAN T, LEVY D, SMTI'H K, PREISINGERA, HAM1LTONS, |lEDGE P, MARKHAMA, ET At.: Identification of a Gene Located at Chromosome 5q21 that is Mutated in Colorectal Cancers. Sc/ence 1991, 521:1366-1370. Cloning and identification of a gene involved in colon cancer, postulated to play a role in polyposis.

KINGCIL SWALNSM, PORTER I., STEINBERG SM, LIPPMANME, GELM&N EP: Heterogeneous Expression of erbB-2 Messenger RNA in Human Breast Cancer. Cancer Res 1989, 49:4185--4191.


BORGA, TANT)ONAK, StGGURDSSONH, CLARKGM, FERNO M, FUQUASAW, KIIANT)ERD, MeGUmEWI: HER-2/neu Amplification Predicts Poor Survival in Node-positive Breast Cancer. Cancer Res 1990, 50:4332--4337.

18. ..


WRIGHTC, /LNGUS B, NICHOtSON S, SAINSBURYJR, CAnLNSJ GULUCK WJ, KELLYP, HARMSAL, HORNE CH: Expression of oerbB20ncoprotein: a Prognostic Indicator in Human Breast Cancer. Cancer Res 1989, 49:2067.


MULLER~(TJ, SIh.'N E, PATrENGALE PK, WALLACE R, LEDER P: Single-step Induction of Mammary Adenocarcinoma in Transgenic Mice Bearing the Activated c-neu Oncogene. Cell 1988, 54:105-115.


CLARKGM, McGUIRE WL: Follow-up Study of HER-2/neu Amplification in Primary Breast Cancer. Cancer Res 1991, 51:944-948.


PARKESHC, LILLYCROPK, HOWELLA, CRAIGRK: C-erbB2 mlLNA Expression in Human Breast Turnouts: Comparison with c-erbB2 DNA Amplification and C_x)rrelation with Prognosis. Br J Cancer 1990, 61:39-45.

17. ,

NISHISHOJ, NAK&MURAY, bLryosm Y, M ~ Y, ANDOH, HORU.4, KOYAMA K, UTSUNOMIYAJ, BABA S, HEDGE P, ETAL: Mutations of Chromosome 5q21 Genes in FAP and Colorectal Cancer Patients. Science 1991, 253:665-669. Cloning of gene~ within the FAP locus, and identification of a candidate gene for APC See also [19°°-21oo]. 19. °.

KINZERKW, NtLBERTMC, SU L-K, VOGELSTEINB, BRYAN"I'M, LEVYDB, SMrrH KJ, PRELSlNGERAC, HEDGE P, MCKEO~'IE D, LeT at.: Identification of FAP Locus Genes from Chromosome 5q21. Sc/ence 1991, 253:661--665. Demonstration that APC is probably causative in FAP, and that both MCCand FAP play a role in colorectal cancer. See [20~%21oo]. 20. **

GRODENJ, THtr~xlUS A, SgMo~riz W, CARLSONM, GELBERT L ALBERTSON H, JOSLYN G, STL~XN"~J, SPIRIO L, ROBERTSON M, Er at.: Identification and Characterization of the Familial Adcnomatous Polyposis Coli Gene. Cell 1991, 66:589-600.

Genetic basis of cancer Klinger 38.

MUSHYLC: Estrogen Receptor Variants in Human Breast Cancer. Mol Cell Endocrinol 1990, 74:C83--C86.


BORGA, BALDETORP B, FERNO M, KIILANDERD, OLSSON H, SIG~N H: ErbB2 Amplification in Breast Cancer with a High Rate of Proliferation. Oncogene 1991, 6:.137-143.


ZUPPANP, HALLJM, LEE MK, PONGLIXlI'MONGKOLM, K~G MC: Possible Linkage of Estrogen Receptor Gene to Breast Cancer in a Family with Late-onset Disease. Am J Hum Genet 1991, 48:1065-1068.


BEVIIACQUAG: NM23 Gene Expression and Human Breast Cancer Metastases. Path Biol 1990 38:774-775.


HENNESSYC, HENRYJA, MAY FEB, WF_.SaXEYBR, ANGUS B, LE~U~D TWJ: Expression of the Antimetastic Gene rim23 in Human B r a t Cancer:. an Association with Good Prognosis. J Nail Cancer lint 1991, 83:281-285.




DNA Aneupioldy in Primary Human Breast Cancer. Proc Natl Acad Sci USA 1991, 88:3847-3851. 47.



KING M-C: Linkage of Early-onset Familial Breast Cancer to

Chromosome 17q21. Science 1990, 250:1684-1689. Identification by linkage anab~is of a predisposing locus for breast cancer. 49.


Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms. Science 1990, 250:1233-1238. Demonstration that a germ line mutation o f p 5 3 is responsible for increased susceptibility to cancer, including breast cancer, in Li.Fraumani famines. 44.

SATO T, TANIGAMI A, YAMAKAWAK, AKIYAMAF, KASUMI F, SAKAMOTOG, NAKAm.mAY: Allelotype of Breast Cancer:. Cumulative AUele Losses Promote Tumor Progression in Primary Breast Cancer. Cancer Res 1990, 50:7184-.7189.


Bm.KEKJ, IGGS R, G A ~ N J, L~'E DP: Genetic and Immunochemical Analysis of Mutant p 5 3 in Human Breast Cancer Cell Lines. Oncogene 1990, 5:893-899.


CHENL-C, NEUBAUERA, KUmSUW, WALDMANFM, I/UNG B-M, GOODSON W, GOLDMANES, MOORE D, BAIAZS M, LIu E, ET AL: Loss of Heterozygosity on the Short Arm of Chromosome 17 is Associated with High Proliferative Capacity and

CROPPCS, I~EREAU R, C&V,PBELLG, CH&~,iPEh'EMH, R: LOSS of Heteroz'ygosiry on Chromosomes 17 and 18 in Breast Carcinoma: Two Additional Regions Identified. Pr0c Naa Acad Sci USA 1990, 87:7737-7741.

BORRESENA-L, OTIX.~AD L, GAUSTADA, ANDERSONTI, HEIKKILA R, JAI-Z",ISENT, "IVErr KM, N~L&','DJM: Amplification and Protein Over-expression of the neu/her.2/c-erbB-2 Protooncogene in Human Breast Carcinomas: Relationship to Loss of Gene Sequences on Chromosome 17, Family History and Prognosis. B r J Cancer 1990, 62:585-590.

50. .

SKOLNICKMH, CANNON-AI.BKIGHT LA, GOLDGAR DE, WARD JH, MARSHALLCJ, SHUMANNGB, HOGLE H, MCWHORTERWP, WPaGHT EC, TRAN "I'D, E'r at.: Inheritance of Proliferative Breast Disease in Breast Cancer Kindreds. Science 1990, 250:1715--1720. Presents e~dence suggesting that benign proliferative breast disease may result from a gene that confers a predisposition to breast caner. This might provide an intermediate stage in tumor progression, analognus to poly formation and colorectal cancer. 51.

MARXJ: Possible New Colon Cancer Gene Found. Science 1991, 251:1317.

KW Klinger, Integrated Genetics, 1 Mountain Road, Framingham, Massachusetts 01701, USA.


Genetic basis of cancer.

Tumorigenesis is a heterogeneous process that occurs over a relatively long time span, progressing from a single cell through intermediate stages to g...
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