BRCA1 and BRCA2 Mutations and the Risk for Colorectal Cancer
Sopik, V1, Phelan, C2, Cybulski C3, and Narod, SA1 Affiliations: 1
Women’s College Research Institute, Women’s College Hospital, Familial Breast Cancer
Research, 790 Bay Street, Toronto, Ontario, M5G 1N8, Canada; 2Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33647, USA, 3 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
Corresponding author: Steven A Narod, Women’s College Research Institute, 790 Bay Street, 7th Floor, Toronto, Ontario, Canada M5G 1N8, Tel: 1-416-351-3765, Fax:1-416-351-3767, Email: [email protected]
The author’s declare no conflict of interest.
Key words: BRCA1, BRCA2, colorectal cancer, prevention, colonoscopy, aspirin
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cge.12497
This article is protected by copyright. All rights reserved
Abstract
Women who carry a BRCA1 or BRCA2 mutation are at high risk of breast and ovarian cancer, and may be at moderately increased risk of other cancer types. This review examines studies to date that have evaluated the risk of BRCA1 and BRCA2 mutations for colorectal cancer. Accurate knowledge of colorectal cancer risk in BRCA1/2 carriers is important, because colonoscopy screening can prevent colorectal cancer through the removal of adenomatous polyps. Most studies that have identified an increased risk for colorectal cancer in BRCA1/2 mutation carriers were in high-risk cancer families, while studies that found no association were conducted in specific populations and involved the analysis of founder mutations. A recent prospective study of 7015 women with a BRCA1 or BRCA2 mutation identified significant five-fold increased risk of colorectal cancer among BRCA1 mutation carriers below the age of 50 (SIR = 4.8; 95% CI 2.2 – 9), but not in women with a BRCA2 mutation or in older women. Based on this evidence, women with BRCA1 mutations should be counseled about their increased risk for early-onset colorectal cancer, and offered colonoscopy at three to five year intervals between the ages of 40 to 50 years, and should follow population guidelines thereafter.
This article is protected by copyright. All rights reserved
Introduction
Mutations in several DNA repair genes contribute to the origin of many cancer types [1, 2]. BRCA1 and BRCA2 are crucial proteins involved in homologous recombination, which is the most accurate method of double-stranded DNA break repair [3, 4]. Germline mutations in BRCA1/2 are highly penetrant for breast cancer and ovarian cancer, conferring lifetime risks of up to 85% for breast cancer, and 40% (BRCA1) and 20% (BRCA2) for ovarian cancer [5, 6]. BRCA mutations have also been associated with lymphoma, leukemia, melanoma, prostate, pancreatic, stomach, and colorectal cancer [7, 8] but the magnitude of the relevant risks are not clear. Colorectal cancer is common and is often observed in hereditary breast and ovarian cancer families [9-11], but studies that have attempted to determine the excess incidence of colorectal cancer in BRCA mutation carriers have conflicting results and there are no guidelines for colorectal cancer screening among carriers [12]. Through colorectal cancer screening, precancerous lesions (adenomatous polyps), may be identified and removed, thus preventing invasive cancers. The gold standard is colonoscopy, because polyps can be removed with polypectomy during the initial procedure [13].
The average lifetime risk for colorectal cancer is approximately 6% in North America,
is similar in men and women, and 90% of sporadic colorectal cancers are diagnosed after age 50 [14]. Established guidelines for individuals at average risk recommend screening colonoscopy once every ten years beginning at age 50 [12, 15]. One of the most important risk factors for colorectal cancer is a positive family history; approximately 10% of individuals in the general population have a first-degree relative affected by colorectal cancer and thereby carry a two to four-fold increased risk for colorectal cancer [16]. The risk is
This article is protected by copyright. All rights reserved
increased further if multiple first-degree relatives are affected, or if a relative is diagnosed at age 50 or below. Approximately 20-30% of colorectal cancer cases occur in familial clusters [17], but only about 5% can be attributed to inherited conditions with a clear genetic definition [18], and for which guidelines have been established. These familial syndromes are caused by rare mutations in highly penetrant genes, which include MLH1, MSH2, MSH6 and PMS2 (for Lynch syndrome/HNPCC), APC (Familial Adenomatous Polyposis), STK11 (Peutz-Jeghers syndrome), MUTYH (MUTYH-associated polyposis), PTEN (Cowden syndrome), BMPRIA and SMADH4 (Juvenile Polyposis). After a mutation is identified, carriers are enrolled in high-risk screening programs [12, 15]. The majority of familial colorectal cancers are not explained by mutations in one of the high-risk genes. For these individuals, screening is primarily based on family history [12, 15]. With advances in sequencing technology and the introduction of multi-gene panels, genetic testing is extending from only the inclusion of established high-risk genes to genes with moderate and unknown risks for colon (and other) cancers. Several clinical laboratories currently offer gene panel testing, but for many of the genes in a panel there are no guidelines for screening or prevention and counselling is difficult [19, 20]. BRCA1 and BRCA2 are included in many cancer risk panels. Should BRCA1/2 be included on colorectal cancer risk panels? In some cases a BRCA1 or BRCA2 mutation will be found among men and women with colon cancer and it is unclear how a positive test in this context could be used to improve the clinical management of colorectal cancer. To address these issues, the prevalence and penetrance of BRCA1/2 mutations for colorectal cancer must be determined, and efforts are required to educate clinicians and genetic counselors with accurate information on the associated risks and appropriate strategies for prevention.
This article is protected by copyright. All rights reserved
What is the penetrance of BRCA1/2 mutations for colorectal cancer? Different approaches have been used to determine the risk of colorectal cancer associated with BRCA1/2 mutations. These include studies of families with multiple cancers and of individual cases of colon cancer [7, 21-24]. The approaches used in these studies included prospective cohort, retrospective cohort and kin-cohort designs (summarized in table 1), association/case-control designs (table 2), and family-based designs (table 3). In general most of the positive results (relative risks two to four) were derived from studies of high-risk cancer families, whereas studies of unselected colon cancer patients generally found no significantly increased risks for either BRCA1 or BRCA2 [25-32]. The validity of these studies must be assessed for precision and statistical power, which is determined in large part by the number of exposed cases identified (colon cases with mutations), and for bias, in order for conclusions to be made.
The prospective cohort study The gold standard for estimating incidence is the prospective cohort study [33]. Prospective studies have fewer potential sources of bias compared to retrospective studies, as none of the subjects have the outcome of interest at the time the study is initiated when baseline data is collected, and the events can be collected as they occur. However, given that both the exposure (BRCA1/2 mutation) and outcome (colorectal cancer) are rare, the size of a cohort required for an accurate determination of risk is large. To date, only one prospective cohort study has been conducted and published in 2014, the results of which indicate an approximately four-fold increased risk of early-onset colorectal cancer in female BRCA1 mutation carriers. In this study, Phelan et al. followed 7015 women with a BRCA1 or BRCA2 mutation, ascertained from 50 centers across the USA, Canada, and Europe [24]. The women
This article is protected by copyright. All rights reserved
were followed for an average of 5.5 years (minimum two years) for incident cases of colorectal cancer. The risk of colorectal cancer in BRCA1/2 mutation carriers was estimated with standardized incidence ratio (SIR), which is the ratio of observed cancer incidence in carriers to the expected number of colorectal cancer cases, based on population cancer rates. Twenty-one incident colorectal cancer cases were observed among all mutation carriers, which was similar to the 23.6 cases expected. However, eight of the 21 colorectal cancer cases in carriers were diagnosed in women below the age of 50, compared to 2.10 expected in the general population (SIR: 3.81; 95% CI: 1.77-7.2; p = 0.001). All eight colorectal cancer cases were identified in women with a BRCA1 mutation, compared to 1.68 expected (SIR: 4.76; 95% CI: 2.21-9; p
Sopik, V1, Phelan, C2, Cybulski C3, and Narod, SA1 Affiliations: 1
Women’s College Research Institute, Women’s College Hospital, Familial Breast Cancer
Research, 790 Bay Street, Toronto, Ontario, M5G 1N8, Canada; 2Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33647, USA, 3 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
Corresponding author: Steven A Narod, Women’s College Research Institute, 790 Bay Street, 7th Floor, Toronto, Ontario, Canada M5G 1N8, Tel: 1-416-351-3765, Fax:1-416-351-3767, Email: [email protected]
The author’s declare no conflict of interest.
Key words: BRCA1, BRCA2, colorectal cancer, prevention, colonoscopy, aspirin
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cge.12497
This article is protected by copyright. All rights reserved
Abstract
Women who carry a BRCA1 or BRCA2 mutation are at high risk of breast and ovarian cancer, and may be at moderately increased risk of other cancer types. This review examines studies to date that have evaluated the risk of BRCA1 and BRCA2 mutations for colorectal cancer. Accurate knowledge of colorectal cancer risk in BRCA1/2 carriers is important, because colonoscopy screening can prevent colorectal cancer through the removal of adenomatous polyps. Most studies that have identified an increased risk for colorectal cancer in BRCA1/2 mutation carriers were in high-risk cancer families, while studies that found no association were conducted in specific populations and involved the analysis of founder mutations. A recent prospective study of 7015 women with a BRCA1 or BRCA2 mutation identified significant five-fold increased risk of colorectal cancer among BRCA1 mutation carriers below the age of 50 (SIR = 4.8; 95% CI 2.2 – 9), but not in women with a BRCA2 mutation or in older women. Based on this evidence, women with BRCA1 mutations should be counseled about their increased risk for early-onset colorectal cancer, and offered colonoscopy at three to five year intervals between the ages of 40 to 50 years, and should follow population guidelines thereafter.
This article is protected by copyright. All rights reserved
Introduction
Mutations in several DNA repair genes contribute to the origin of many cancer types [1, 2]. BRCA1 and BRCA2 are crucial proteins involved in homologous recombination, which is the most accurate method of double-stranded DNA break repair [3, 4]. Germline mutations in BRCA1/2 are highly penetrant for breast cancer and ovarian cancer, conferring lifetime risks of up to 85% for breast cancer, and 40% (BRCA1) and 20% (BRCA2) for ovarian cancer [5, 6]. BRCA mutations have also been associated with lymphoma, leukemia, melanoma, prostate, pancreatic, stomach, and colorectal cancer [7, 8] but the magnitude of the relevant risks are not clear. Colorectal cancer is common and is often observed in hereditary breast and ovarian cancer families [9-11], but studies that have attempted to determine the excess incidence of colorectal cancer in BRCA mutation carriers have conflicting results and there are no guidelines for colorectal cancer screening among carriers [12]. Through colorectal cancer screening, precancerous lesions (adenomatous polyps), may be identified and removed, thus preventing invasive cancers. The gold standard is colonoscopy, because polyps can be removed with polypectomy during the initial procedure [13].
The average lifetime risk for colorectal cancer is approximately 6% in North America,
is similar in men and women, and 90% of sporadic colorectal cancers are diagnosed after age 50 [14]. Established guidelines for individuals at average risk recommend screening colonoscopy once every ten years beginning at age 50 [12, 15]. One of the most important risk factors for colorectal cancer is a positive family history; approximately 10% of individuals in the general population have a first-degree relative affected by colorectal cancer and thereby carry a two to four-fold increased risk for colorectal cancer [16]. The risk is
This article is protected by copyright. All rights reserved
increased further if multiple first-degree relatives are affected, or if a relative is diagnosed at age 50 or below. Approximately 20-30% of colorectal cancer cases occur in familial clusters [17], but only about 5% can be attributed to inherited conditions with a clear genetic definition [18], and for which guidelines have been established. These familial syndromes are caused by rare mutations in highly penetrant genes, which include MLH1, MSH2, MSH6 and PMS2 (for Lynch syndrome/HNPCC), APC (Familial Adenomatous Polyposis), STK11 (Peutz-Jeghers syndrome), MUTYH (MUTYH-associated polyposis), PTEN (Cowden syndrome), BMPRIA and SMADH4 (Juvenile Polyposis). After a mutation is identified, carriers are enrolled in high-risk screening programs [12, 15]. The majority of familial colorectal cancers are not explained by mutations in one of the high-risk genes. For these individuals, screening is primarily based on family history [12, 15]. With advances in sequencing technology and the introduction of multi-gene panels, genetic testing is extending from only the inclusion of established high-risk genes to genes with moderate and unknown risks for colon (and other) cancers. Several clinical laboratories currently offer gene panel testing, but for many of the genes in a panel there are no guidelines for screening or prevention and counselling is difficult [19, 20]. BRCA1 and BRCA2 are included in many cancer risk panels. Should BRCA1/2 be included on colorectal cancer risk panels? In some cases a BRCA1 or BRCA2 mutation will be found among men and women with colon cancer and it is unclear how a positive test in this context could be used to improve the clinical management of colorectal cancer. To address these issues, the prevalence and penetrance of BRCA1/2 mutations for colorectal cancer must be determined, and efforts are required to educate clinicians and genetic counselors with accurate information on the associated risks and appropriate strategies for prevention.
This article is protected by copyright. All rights reserved
What is the penetrance of BRCA1/2 mutations for colorectal cancer? Different approaches have been used to determine the risk of colorectal cancer associated with BRCA1/2 mutations. These include studies of families with multiple cancers and of individual cases of colon cancer [7, 21-24]. The approaches used in these studies included prospective cohort, retrospective cohort and kin-cohort designs (summarized in table 1), association/case-control designs (table 2), and family-based designs (table 3). In general most of the positive results (relative risks two to four) were derived from studies of high-risk cancer families, whereas studies of unselected colon cancer patients generally found no significantly increased risks for either BRCA1 or BRCA2 [25-32]. The validity of these studies must be assessed for precision and statistical power, which is determined in large part by the number of exposed cases identified (colon cases with mutations), and for bias, in order for conclusions to be made.
The prospective cohort study The gold standard for estimating incidence is the prospective cohort study [33]. Prospective studies have fewer potential sources of bias compared to retrospective studies, as none of the subjects have the outcome of interest at the time the study is initiated when baseline data is collected, and the events can be collected as they occur. However, given that both the exposure (BRCA1/2 mutation) and outcome (colorectal cancer) are rare, the size of a cohort required for an accurate determination of risk is large. To date, only one prospective cohort study has been conducted and published in 2014, the results of which indicate an approximately four-fold increased risk of early-onset colorectal cancer in female BRCA1 mutation carriers. In this study, Phelan et al. followed 7015 women with a BRCA1 or BRCA2 mutation, ascertained from 50 centers across the USA, Canada, and Europe [24]. The women
This article is protected by copyright. All rights reserved
were followed for an average of 5.5 years (minimum two years) for incident cases of colorectal cancer. The risk of colorectal cancer in BRCA1/2 mutation carriers was estimated with standardized incidence ratio (SIR), which is the ratio of observed cancer incidence in carriers to the expected number of colorectal cancer cases, based on population cancer rates. Twenty-one incident colorectal cancer cases were observed among all mutation carriers, which was similar to the 23.6 cases expected. However, eight of the 21 colorectal cancer cases in carriers were diagnosed in women below the age of 50, compared to 2.10 expected in the general population (SIR: 3.81; 95% CI: 1.77-7.2; p = 0.001). All eight colorectal cancer cases were identified in women with a BRCA1 mutation, compared to 1.68 expected (SIR: 4.76; 95% CI: 2.21-9; p
