Breast Cancer Res Treat (2015) 150:631–635 DOI 10.1007/s10549-015-3340-4
EPIDEMIOLOGY
Cancer risks in Jewish male BRCA1 and BRCA2 mutation carriers Yael Laitman1 • Lital Keinan Boker3,4 • Irena Liphsitz3 • Daphna Weissglas-Volkov2 Shira Litz-Philipsborn1 • Hagit Schayek1 • Eitan Friedman1,2
•
Received: 23 February 2015 / Accepted: 10 March 2015 / Published online: 19 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Cancer risks and tumor types in male BRCA1 and BRCA2 mutation carriers are still unsettled. Cancer risks in men who were found to harbor a BRCA1 (n = 150) or a BRCA2 (n = 88) mutation or both (n = 2) were assessed by cross referencing with data on cancer occurrence in the Israeli National Cancer Registry. Incidence rates in mutation carriers were compared with men who were counseled, genotyped, and found not to harbor the familial mutation (true negative n = 122), and with standardized incidence rates (SIRs). Of 210 cancer-free individuals at initial counseling, 11 cancers were diagnosed after a mean follow-up of 5.06 ± 4.1 years (1064 person/ years) compared with 1/122 in a BRCA true-negative man. The SIR for all BRCA1/2 mutation carriers compared with the rates in the general population were elevated for pancreatic cancer [2.97 (95 % CI 1.83–4.29)] and breast cancer [16.44 (95 % CI 9.65–26.24)]. For prostate cancer these rates were 0.59 (95 % CI 0.4–0.84). Jewish BRCA1/2 mutation carriers are at an increased risk for breast and
Electronic supplementary material The online version of this article (doi:10.1007/s10549-015-3340-4) contains supplementary material, which is available to authorized users. & Eitan Friedman [email protected]; [email protected]; [email protected] 1
The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Tel-Hashomer, Israel
2
The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
3
The Israel National Cancer Registry (INCR), Ministry of Health, Jerusalem, Israel
4
The School of Public Health, Haifa University, Haifa, Israel
pancreatic, but not prostate cancer. These cancer risks and the consequent recommendations, if validated, should be transmitted to carriers at test result disclosure. Keywords BRCA germline mutations Cancer risk Male breast cancer Prostate cancer
Introduction Germline mutations in the BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185) genes are associated with a significantly increased lifetime risk for developing cancer. Women who carry deleterious mutations in either gene are at risk rates for developing breast and ovarian cancer that are up to X6 and X25 of the risk in average risk women, respectively [1]. The risk for developing other cancer types is also reportedly increased, particularly in BRCA2 mutation carriers: pancreatic, gastric, bile duct, ocular, and cutaneous melanoma [2]. Cancer types and cancer-specific risks for male BRCA mutation carriers are less established compared with female mutation carriers. Specifically, prostate cancer risk has been the topic of conflicting and inconclusive reports, with some claiming that BRCA mutations, especially BRCA2 mutations, are associated with an increased prostate cancer risk [3, 4] while others failed to show an increased risk [5, 6] Male breast cancer risk in BRCA2 mutation carriers has been based on a handful of reports, with reported lifetime risks to be ranging from 6.8 to 8.7 % for male breast cancer by the age of 80 years [7, 8]. Notably, male BRCA1 mutation carriers were not reported to be at an increased risk for developing any cancer type [9]. Liede and co-workers [10] reported elevated risks for male BRCA1 and BRCA2 mutation carriers for developing additional cancer types such as gastric, pancreatic,
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bile duct cancers, skin, and ocular melanoma. Yet, these elevated risks were based on a handful of cases in a limited number of families. Risch et al. [11] reported that among Canadian BRCA1 mutation carriers, the risks for developing testicular cancer are also increased. The spectrum of BRCA1 and BRCA2 mutations in Jewish individuals is limited, with a few predominant and recurring mutations that are detected in high risk families. Specifically, three mutations in BRCA1 (185delAG 5382InsC) and BRCA2 (6174delT) account for the majority of high risk, BRCA-positive families of Jewish Ashkenazi origins [12]. In other Jewish, non-Ashkenazi populations, there are also a few recurring mutations [13], making mutational analysis in Israeli high risk families more efficient and streamlined than in most world populations. Moreover, as part of the health basket for all Israeli citizens, any person with at least 10 % chance of being a BRCA mutation carrier, is eligible for genetic counseling and testing for these predominant and recurring mutations (www.health.gov.il). The present study was carried out in order to assess cancer risks in male BRCA1 and BRCA2 mutation carriers taking advantage of the limited spectrum of BRCA1 BRCA2 mutations in the Jewish population in Israel.
Methods Patient identification and recruitment All men who were referred for genetic counseling and testing at the Oncogenetics unit, Sheba Medical Center, Tel-Hashomer from January 1, 1996 to December 31, 2013, who were found to harbor pathogenic mutations in the BRCA1 or BRCA2 genes were eligible for participation. The reasons for referral were either a personal history of cancer, or having a significant family history of breast and ovarian cancer, as detailed previously [13], or having a family member with a known BRCA1/BRCA2 mutation and a 25 % chance or more for being a mutation carrier. At genetic counseling, demographic and personal medical history data, as well as lifestyle and exposure data were collected from all participants, and a pedigree was drawn. The study was approved by the local IRB and each participant gave an informed consent.
Breast Cancer Res Treat (2015) 150:631–635
Jewish population (supplementary Table 1) in Israel in a single PCR reaction. The NanoCHIPÒ microarray technology is based on hybridization of DNA strands to probes on a chip array and the use of fluorescently labeled reporter for detecting the presence or absence of a particular mutation. Noteworthy, the validity of this assay in detecting each of the mutation was conformed (Friedman E-unpublished data). Each mutation was validated by an independent DNA genotyping using Sanger sequencing. Of note, all mutations genotyped by the NanoChip (including the ones more commonly detected in the non-Ashkenazi population) are confirmed pathogenic mutations. Cross referencing with the database of the Israeli National Cancer Registry Cancer diagnoses and dates of these diagnoses were obtained from the Israeli National Cancer Registry (INCR) by cross referencing the ID numbers of all participants with the list of cancer diagnoses reported to the INCR. The INCR, a passive, national, population-based cancer registry, was established in 1960. Since 1982 reporting on all cancer cases to the INCR is compulsory by law. The INCR completeness with respect to solid tumors is over 93 % [14]. The expected rates of developing each cancer type for the study participants were taken from the published database of the Israeli Health ministry and the INCR database by age standardized rates. These data are updated to December 31, 2011. Statistical analysis Standardized incidence ratio (SIR) was calculated for each cancer by comparing the observed incidence to the expected incidence in the general population in Israel (as calculated from the INCR data by the end of 2011). SIR and confidence intervals (CI) for each cancer were calculated for BRCA1 and BRCA2 combined. The observed/expected ratio was calculated in five-year periods to minimize the diversity in age-related cancer incidence rates. Comparison of cancer incidence rates between BRCA1 carriers with BRCA2 carriers and between carriers and true negatives was carried out using Chi square test.
Results Genotyping for the predominant mutations in BRCA1 BRCA2
Participants’ characteristics
Was carried out using either a PCR enzymatic digestionbased assay, as previously described [13] or a multiplexed assay by The NanoCHIPÒ electronic microarray. The latter assay detects all recurring mutations in the Jewish and non
Overall, the case group encompassed 240 men who were counseled, genotyped, and found to be BRCA1 (n = 150) BRCA2 (n = 88) mutation carriers and two men carried both a BRCA1 and a BRCA2 mutation. As one control
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group we used data derived from 122 men who were counseled, genotyped because of a known familial mutation, and found not to harbor the familial mutation (= true negative). Thus, a total of 362 participants were included in the study. Of these, 30 participants, all mutation carriers, were diagnosed with cancer at the time of initial counseling and testing, and the rest (n = 210) were cancer free at the time of initial counseling. Age range at counseling for all participants was 22–88 years (48.7 ? 14.2 years; mean ? SD). Age range for BRCA1, BRCA2, and noncarriers were similar (Supplementary Table 1). Among all study participants the majority (n = 282–77.9 %) were of Ashkenazi origin, and of the non-Ashkenazi participants, there were 25 Iraqi and Iranian, 15 of Balkan countries and 30 were of mixed Ashkenazi–non-Ashkenazi origin. Supplementary Table 1 details the ethnic origin of all study participants and the precise mutations detected. Prospective cancer risks Among BRCA1 and BRCA2 mutation carriers who were cancer free at the time of counseling (n = 210), 11 cancer diagnoses in 11 carriers over the entire study period (mean follow-up of 5.06 ± 4.1 years—1064 men/years). Among true negative controls (n = 122), one person was diagnosed with pancreatic cancer, five years after initial counseling. Cancer types and age at diagnosis for carriers and true negative controls are shown in supplementary Table 2. Cancer risks compared with the general population To assess cancer risk in mutation carriers compared with the general population in Israel, the SIRs for all mutation carriers, regardless of their health status at the time of initial counseling were computed. The SIRs were elevated for pancreatic cancer [2.97 (95 %CI 1.83–4.29)] and breast cancer [16.44 (95 % CI 9.65–26.24)]. However, for prostate cancer these rates were 0.59 (95 % CI 0.40–0.84). Given the small number of cancer diagnoses at follow-up in the 210 initially cancer-free participants, formal statistical analyses restricted to that group were not attempted. Cancer incidence within study population Cancer incidence rates in BRCA1/2 carriers combined compared with, non-carrier true negatives revealed no statistically significant differences in cancer incidence or the relative risk, for all cancers (Table 1) as well as specific cancer types (Table 2). However, BRCA2 mutation carriers were more frequently diagnosed with any cancer type compared with BRCA1 mutation carriers (Table 1) both at time of counseling (p = 0.047), and for cancer diagnosed
633
after counseling (p = 0.002) and overall (p = 0.0019). Similarly, the relative risk (RR) for developing any cancer type was significantly elevated for BRCA2 mutation carriers compared with BRCA1 mutation carriers: at time of counseling (RR 2.36,1.21–4.58 95 % CI, p = 0.011), after counseling (RR 8.68, 1.92–39.11 95 % CI, p = 0.004), and overall (RR 3.12, 1.87–5.20 95 % CI, p \ 0.0001) (Table 1). Relative risk for specific cancers (Table 2) showed an elevated risk in BRCA2 carriers for prostate cancer (RR 4.54, 1.23–16.68 95 % CI, p = 0.022), a marginal, statistically non-significant risk for breast cancer (RR 6.81, 0.77-60.04 95 % CI, p = 0.083) and no difference in risk for pancreatic cancer (RR 2.13, 0.58–7.72 95 % CI, p = 0.24).
Discussion In the present study, the risk for developing pancreatic and breast cancer in Jewish male BRCA1and BRCA2 mutation carriers was significantly elevated compared with the expected rates in the general population, whereas the risk for developing prostate cancer was not. The results regarding the elevated pancreatic and breast cancer risks in male BRCA mutation carriers are in line with some of the previously published data derived from other, ethnically heterogeneous populations with a more diverse spectrum of germline BRCA1 BRCA2 mutations [2, 7–10]. The current study does not support the putative elevated prostate cancer risk attributed by some previous studies to male BRCA carriers (e.g. [3, 4, 15, 16]). Moreover, there was no overall increased risk for developing other cancer types that were reported among male BRCA carriers in other populations: colon cancer, malignant melanoma, testicular cancer (reviewed by Mahon [17]). The reasons for these seemingly inconsistent results may be attributed to several factors: the short follow-up of the current study, the limited number of participants and cancer diagnosed at follow-up, and the narrow mutational spectrum in the present study or the different study designs of the present study compared with previous reports. The risk for developing pancreatic cancer in female BRCA1 and BRCA2 carriers have also been reported to be elevated compared with non carriers. Thompson and coworkers (9) reported cumulative lifetime risks for female and male BRCA1 carriers: 1,26 (95 % CI 0.92–1.72) and 1.16 (95 % CI 0.83–1,61), respectively, both are statistically insignificant. The Breast cancer linkage consortium (2) reported the cumulative risk for developing pancreatic cancer by the age of 80 years in BRCA2 carriers in females and males—2.3 (95 % CI 1.1–3.5) and 3.2 (95 % CI 1.6–4.9). Mersch and co-workers [18] reported that the SIR for developing pancreatic cancer were elevated for BRCA2
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Table 1 Cancer rate comparisons between BRCA1, BRCA2 mutation carriers, and true negatives
Affected men at time of counseling
BRCA1
BRCA2
Non BRCA
Pv
BRCA1 ? BRCA2
Non BRCA
Pv
RR
13/150
18/88
14/122
0.01
30/240
14/122
0.86
1.09a
1/108
0.0001
0.77
2/137
9/71
5.71
0.74–43.65
0.093
13/150
18/88
0.047
2.36b
1.21–4.58
0.011
Affected men after counseling
2/137
9/71
0.002
8.68b
1.92–39.11
0.004
All affected men
15/150
26/88
1.39a
0.80–2.40
0.24
All affected men
15/150
26/88
0.001
2.95b
1.65–5.26
0.0002
a
41/240
15/122
0.068
0.6–1.8
Affected men after counseling
0.002
1/108
a
Pv
Affected men at time of counseling
15/122
11/208
95 % CI
0.30
Cancers at counseling Cancers at counseling
16/150 16/150
24/88 24/88
16/122
0.013 0.008
40/240
16/122
0.54
1.27 2.55b
0.74–2.17 1.43–4.54
0.38 0.001
Cancers after counseling
2/137
9/71
1/108
0.0001
11/208
1/108
0.068
5.71a
0.74–43.65
0.093
All cancers
18/150
33/88
17/122
0.0002
51/240
17/122
0.15
1.52a
0.92–2.52
0.100
All cancers
18/150
33/88
3.12b
1.87–5.20
\0.0001
0.0005
a
RR calculated for BRCA1 and BRCA2 combined versus Non BRCA
b
RR calculated for BRCA1 versus BRCA2
Table 2 Cancer rate comparisons for prostate, breast, and pancreatic cancer between BRCA1, BRCA2 mutation carriers and true negatives
Prostate
BRCA1
BRCA2
Non BRCA
Pv
BRCA1 ? BRCA2
Non BRCA
Pv
RR
3/150
8/88
3/122
0.022
11/240
3/122
0.40
1.86a
Prostate
3/150
8/88
Breast
1/150
4/88
Breast
1/150
4/88
Pancreas
4/150
5/88
Pancreas
4/150
5/88
0.024 1/122
0.060
5/240
0.66
0.049 2/122
0.254
9/240
0.303
a
RR calculated for BRCA1 and BRCA2 combined versus Non BRCA
b
RR calculated for BRCA1 versus BRCA2
mutation carriers in both males (n = 33) and females (n = 426): males -82.5 (95 % CI 39.5–151.8) and females 13.8 (95 % CI 6.3–26.1). Thus, there is an increased risk for pancreatic cancer in BRCA2 carriers that is gender independent. It is clear that the overall risk for developing cancer is attributable to male BRCA2 mutations more frequently than to BRCA1 mutations. Notably, Moran and co-workers (15) could not show any increased cancer risk for male BRCA1 carriers. Yet, the fact that there are no differences between the rates in conferring pancreatic cancer may signify that both genes are associated with a similar elevated pancreatic cancer risk. One caveat is the fact that some of the analyses included all male carriers, regardless of their health status at counseling, cancer affected and healthy men. However, given the paucity of cancer diagnoses during follow-up, formal statistical analyses were not attempted. The implications of the current study are that elevated pancreatic and breast cancer risks should be conveyed to the
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1/122 2/122
0.34
95 % CI
Pv
0.52–6.55
0.33
b
4.54
1.23–16.68
0.022
2.54a
0.30–21.51
0.39
6.81b
0.77–60.04
0.083
2.28a
0.50–10.42
0.28
2.13b
0.58–7.72
0.24
counseled individuals. Even if confirmed by larger prospective studies, the personal clinical implications to male mutation carriers are limited. There are no studies to support the efficiency and clinical utility of any early detection schemes for male breast cancer. Furthermore, there are no proven efficient methods for early detection of pancreatic cancer. Yet, some centers recommend performing an annual trans-esophageal ultrasound to enhance the possibility of early detection of pancreatic cancer, as suggested by limited studies [19, 20] and an expert opinion [21]. The limitations of this study should be specified: this is a study from a single medical center in Israel, which analyzed cancer types and risks for a small number of BRCA carriers of a limited number of recurring mutations. The small number of carriers and the short follow-up makes detection of rare cancers with moderate penetrance unlikely to be detected. Moreover, since cancer risk is clearly associated with mutation location in breast and ovarian cancer [22] and claims for mutation location effects have
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been made about prostate cancer as well [22], these caveats need to be borne in mind and the results should be interpreted with caution. In conclusion, cancer risk for Jewish male BRCA mutation carriers seems to encompass primarily breast and pancreatic cancer and not prostate cancer. An expansion and validation of these data to other populations seems warranted. Acknowledgments This work was in part funded by a Grant from the Israeli cancer association through the Israeli consortium for inherited cancer. We wish to acknowledge the assistance of the Meirav Comprehensive breast cancer center team at the Sheba Medical Center for assistance in this study. Conflict of interest of interest.
All authors declare that they have no conflicts
Ethical Statement The study was performed after approval by the local IRB (SMC 1492-14) and each participant gave an informed consent.
References 1. Shuen AY, Foulkes WD (2011) Inherited mutations in breast cancer genes–risk and response. J Mammary Gland Biol Neoplasia 16(1):3–15. doi:10.1007/s10911-011-9213-5 2. Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91(15):1310–1316 3. Edwards SM, Kote-Jarai Z, Meitz J, Hamoudi R, Hope Q, Osin P, Jackson R, Southgate C, Singh R, Falconer A, Dearnaley DP, Ardern-Jones A, Murkin A, Dowe A, Kelly J, Williams S, Oram R, Stevens M, Teare DM, Ponder BA, Gayther SA, Easton DF, Eeles RA, Cancer Research UK/Bristish Prostate Group UK Familial Prostate Cancer Study Collaborators; British Association of Urological Surgeons Section of Oncology (2003) Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72(1):1–12 4. Kirchhoff T, Kauff ND, Mitra N, Nafa K, Huang H, Palmer C, Gulati T, Wadsworth E, Donat S, Robson ME, Ellis NA, Offit K (2004) BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res 10(9):2918–2921 5. Agalliu I, Kwon EM, Zadory D, McIntosh L, Thompson J, Stanford JL, Ostrander EA (2007) Germline mutations in the BRCA2 gene and susceptibility to hereditary prostate cancer. Clin Cancer Res 13(3):839–843 6. Fachal L, Go´mez-Caaman˜o A, Celeiro-Mun˜oz C, Peleteiro P, Blanco A, Carballo A, Forteza J, Carracedo A, Vega A (2011) BRCA1 mutations do not increase prostate cancer risk: results from a meta-analysis including new data. Prostate 71(16):1768–1779. doi:10.1002/pros.21394 7. Tai YC, Domchek S, Parmigiani G, Chen S (2007) Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 99(23):1811–1814 8. Evans DG, Susnerwala I, Dawson J, Woodward E, Maher ER, Lalloo F (2010) Risk of breast cancer in male BRCA2 carriers. J Med Genet 47(10):710–711. doi:10.1136/jmg.2009.075176 9. Thompson D, Easton DF, Breast Cancer Linkage Consortium (2002) Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94(18):1358–1365
635 10. Liede A, Karlan BY, Narod SA (2004) Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 22(4):735–742 11. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S, Shaw PA, Narod SA (2006) Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98(23):1694–1706 12. Abeliovich D, Kaduri L, Lerer I, Weinberg N, Amir G, Sagi M, Zlotogora J, Heching N, Peretz T (1997) The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60 % of ovarian cancer and 30 % of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet 60(3):505–514 13. Laitman Y, Simeonov M, Herskovitz L, Kushnir A, ShimonPaluch S, Kaufman B, Zidan J, Friedman E (2012) Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel. Breast Cancer Res Treat 133(3):1153–1157. doi:10.1007/s10549-012-2006-8 14. Fishler Y, Barchana M, Keinan-Boker L, Ifrah A. Blau, S. Cancer in Israel. Trends of incidence and mortality, 1982–2002, and update of selected data, 2004. Israel Center for Disease Control, 2008; Publication #310 [Hebrew] 15. Moran A, O’Hara C, Khan S, Shack L, Woodward E, Maher ER, Lalloo F, Evans DG (2012) Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam Cancer 11(2):235–242. doi:10.1007/s10689-011-9506-2 16. Gallagher DJ, Gaudet MM, Pal P, Kirchhoff T, Balistreri L, Vora K, Bhatia J, Stadler Z, Fine SW, Reuter V, Zelefsky M, Morris MJ, Scher HI, Klein RJ, Norton L, Eastham JA, Scardino PT, Robson ME, Offit K (2010) Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res 16(7):2115–2121. doi:10.1158/1078-0432.CCR-09-2871 17. Mahon SM (2014) Cancer risks for men with BRCA1/2 mutations. Oncol Nurs Forum 41(1):99–101. doi:10.1188/14.ONF.99-101 18. Mersch J, Jackson MA, Park M, Nebgen D, Peterson SK, Singletary C, Arun BK, Litton JK (2015) Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 121(2):269–275. doi:10.1002/cncr.29041 19. Sud A, Wham D, Catalano M, Guda NM (2014) Promising outcomes of screening for pancreatic cancer by genetic testing and endoscopic ultrasound. Pancreas 43(3):458–461. doi:10.1097/ MPA.0000000000000052 20. Lami G, Biagini MR, Galli A (2014) Endoscopic ultrasonography for surveillance of individuals at high risk for pancreatic cancer. World J Gastrointest Endosc 6(7):272–285. doi:10.4253/wjge.v6.i7.272 21. Canto MI, Harinck F, Hruban RH, Offerhaus GJ, Poley JW, Kamel I, Nio Y, Schulick RS, Bassi C, Kluijt I, Levy MJ, Chak A, Fockens P, Goggins M, Bruno M, International Cancer of Pancreas Screening (CAPS) Consortium (2014) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 62(3):339–347. doi:10.1136/ gutjnl-2012-303108 22. Lubinski J, Phelan CM, Ghadirian P, Lynch HT, Garber J, Weber B, Tung N, Horsman D, Isaacs C, Monteiro AN, Sun P, Narod SA (2004) Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer 3(1):1–10 23. Cybulski C, Go´rski B, Gronwald J, Huzarski T, Byrski T, Debniak T, Jakubowska A, Wokołorczyk D, Gliniewicz B, Sikorski A, Stawicka M, Godlewski D, Kwias Z, Antczak A, Krajka K, Lauer W, Sosnowski M, Sikorska-Radek P, Bar K, Klijer R, Romuald Z, Małkiewicz B, Borkowski A, Borkowski T, Szwiec M, Posmyk M, Narod SA, Lubin´ski J (2008) BRCA1 mutations and prostate cancer in Poland. Eur J Cancer Prev 17(1):62–66
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EPIDEMIOLOGY
Cancer risks in Jewish male BRCA1 and BRCA2 mutation carriers Yael Laitman1 • Lital Keinan Boker3,4 • Irena Liphsitz3 • Daphna Weissglas-Volkov2 Shira Litz-Philipsborn1 • Hagit Schayek1 • Eitan Friedman1,2
•
Received: 23 February 2015 / Accepted: 10 March 2015 / Published online: 19 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Cancer risks and tumor types in male BRCA1 and BRCA2 mutation carriers are still unsettled. Cancer risks in men who were found to harbor a BRCA1 (n = 150) or a BRCA2 (n = 88) mutation or both (n = 2) were assessed by cross referencing with data on cancer occurrence in the Israeli National Cancer Registry. Incidence rates in mutation carriers were compared with men who were counseled, genotyped, and found not to harbor the familial mutation (true negative n = 122), and with standardized incidence rates (SIRs). Of 210 cancer-free individuals at initial counseling, 11 cancers were diagnosed after a mean follow-up of 5.06 ± 4.1 years (1064 person/ years) compared with 1/122 in a BRCA true-negative man. The SIR for all BRCA1/2 mutation carriers compared with the rates in the general population were elevated for pancreatic cancer [2.97 (95 % CI 1.83–4.29)] and breast cancer [16.44 (95 % CI 9.65–26.24)]. For prostate cancer these rates were 0.59 (95 % CI 0.4–0.84). Jewish BRCA1/2 mutation carriers are at an increased risk for breast and
Electronic supplementary material The online version of this article (doi:10.1007/s10549-015-3340-4) contains supplementary material, which is available to authorized users. & Eitan Friedman [email protected]; [email protected]; [email protected] 1
The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Tel-Hashomer, Israel
2
The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
3
The Israel National Cancer Registry (INCR), Ministry of Health, Jerusalem, Israel
4
The School of Public Health, Haifa University, Haifa, Israel
pancreatic, but not prostate cancer. These cancer risks and the consequent recommendations, if validated, should be transmitted to carriers at test result disclosure. Keywords BRCA germline mutations Cancer risk Male breast cancer Prostate cancer
Introduction Germline mutations in the BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185) genes are associated with a significantly increased lifetime risk for developing cancer. Women who carry deleterious mutations in either gene are at risk rates for developing breast and ovarian cancer that are up to X6 and X25 of the risk in average risk women, respectively [1]. The risk for developing other cancer types is also reportedly increased, particularly in BRCA2 mutation carriers: pancreatic, gastric, bile duct, ocular, and cutaneous melanoma [2]. Cancer types and cancer-specific risks for male BRCA mutation carriers are less established compared with female mutation carriers. Specifically, prostate cancer risk has been the topic of conflicting and inconclusive reports, with some claiming that BRCA mutations, especially BRCA2 mutations, are associated with an increased prostate cancer risk [3, 4] while others failed to show an increased risk [5, 6] Male breast cancer risk in BRCA2 mutation carriers has been based on a handful of reports, with reported lifetime risks to be ranging from 6.8 to 8.7 % for male breast cancer by the age of 80 years [7, 8]. Notably, male BRCA1 mutation carriers were not reported to be at an increased risk for developing any cancer type [9]. Liede and co-workers [10] reported elevated risks for male BRCA1 and BRCA2 mutation carriers for developing additional cancer types such as gastric, pancreatic,
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632
bile duct cancers, skin, and ocular melanoma. Yet, these elevated risks were based on a handful of cases in a limited number of families. Risch et al. [11] reported that among Canadian BRCA1 mutation carriers, the risks for developing testicular cancer are also increased. The spectrum of BRCA1 and BRCA2 mutations in Jewish individuals is limited, with a few predominant and recurring mutations that are detected in high risk families. Specifically, three mutations in BRCA1 (185delAG 5382InsC) and BRCA2 (6174delT) account for the majority of high risk, BRCA-positive families of Jewish Ashkenazi origins [12]. In other Jewish, non-Ashkenazi populations, there are also a few recurring mutations [13], making mutational analysis in Israeli high risk families more efficient and streamlined than in most world populations. Moreover, as part of the health basket for all Israeli citizens, any person with at least 10 % chance of being a BRCA mutation carrier, is eligible for genetic counseling and testing for these predominant and recurring mutations (www.health.gov.il). The present study was carried out in order to assess cancer risks in male BRCA1 and BRCA2 mutation carriers taking advantage of the limited spectrum of BRCA1 BRCA2 mutations in the Jewish population in Israel.
Methods Patient identification and recruitment All men who were referred for genetic counseling and testing at the Oncogenetics unit, Sheba Medical Center, Tel-Hashomer from January 1, 1996 to December 31, 2013, who were found to harbor pathogenic mutations in the BRCA1 or BRCA2 genes were eligible for participation. The reasons for referral were either a personal history of cancer, or having a significant family history of breast and ovarian cancer, as detailed previously [13], or having a family member with a known BRCA1/BRCA2 mutation and a 25 % chance or more for being a mutation carrier. At genetic counseling, demographic and personal medical history data, as well as lifestyle and exposure data were collected from all participants, and a pedigree was drawn. The study was approved by the local IRB and each participant gave an informed consent.
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Jewish population (supplementary Table 1) in Israel in a single PCR reaction. The NanoCHIPÒ microarray technology is based on hybridization of DNA strands to probes on a chip array and the use of fluorescently labeled reporter for detecting the presence or absence of a particular mutation. Noteworthy, the validity of this assay in detecting each of the mutation was conformed (Friedman E-unpublished data). Each mutation was validated by an independent DNA genotyping using Sanger sequencing. Of note, all mutations genotyped by the NanoChip (including the ones more commonly detected in the non-Ashkenazi population) are confirmed pathogenic mutations. Cross referencing with the database of the Israeli National Cancer Registry Cancer diagnoses and dates of these diagnoses were obtained from the Israeli National Cancer Registry (INCR) by cross referencing the ID numbers of all participants with the list of cancer diagnoses reported to the INCR. The INCR, a passive, national, population-based cancer registry, was established in 1960. Since 1982 reporting on all cancer cases to the INCR is compulsory by law. The INCR completeness with respect to solid tumors is over 93 % [14]. The expected rates of developing each cancer type for the study participants were taken from the published database of the Israeli Health ministry and the INCR database by age standardized rates. These data are updated to December 31, 2011. Statistical analysis Standardized incidence ratio (SIR) was calculated for each cancer by comparing the observed incidence to the expected incidence in the general population in Israel (as calculated from the INCR data by the end of 2011). SIR and confidence intervals (CI) for each cancer were calculated for BRCA1 and BRCA2 combined. The observed/expected ratio was calculated in five-year periods to minimize the diversity in age-related cancer incidence rates. Comparison of cancer incidence rates between BRCA1 carriers with BRCA2 carriers and between carriers and true negatives was carried out using Chi square test.
Results Genotyping for the predominant mutations in BRCA1 BRCA2
Participants’ characteristics
Was carried out using either a PCR enzymatic digestionbased assay, as previously described [13] or a multiplexed assay by The NanoCHIPÒ electronic microarray. The latter assay detects all recurring mutations in the Jewish and non
Overall, the case group encompassed 240 men who were counseled, genotyped, and found to be BRCA1 (n = 150) BRCA2 (n = 88) mutation carriers and two men carried both a BRCA1 and a BRCA2 mutation. As one control
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group we used data derived from 122 men who were counseled, genotyped because of a known familial mutation, and found not to harbor the familial mutation (= true negative). Thus, a total of 362 participants were included in the study. Of these, 30 participants, all mutation carriers, were diagnosed with cancer at the time of initial counseling and testing, and the rest (n = 210) were cancer free at the time of initial counseling. Age range at counseling for all participants was 22–88 years (48.7 ? 14.2 years; mean ? SD). Age range for BRCA1, BRCA2, and noncarriers were similar (Supplementary Table 1). Among all study participants the majority (n = 282–77.9 %) were of Ashkenazi origin, and of the non-Ashkenazi participants, there were 25 Iraqi and Iranian, 15 of Balkan countries and 30 were of mixed Ashkenazi–non-Ashkenazi origin. Supplementary Table 1 details the ethnic origin of all study participants and the precise mutations detected. Prospective cancer risks Among BRCA1 and BRCA2 mutation carriers who were cancer free at the time of counseling (n = 210), 11 cancer diagnoses in 11 carriers over the entire study period (mean follow-up of 5.06 ± 4.1 years—1064 men/years). Among true negative controls (n = 122), one person was diagnosed with pancreatic cancer, five years after initial counseling. Cancer types and age at diagnosis for carriers and true negative controls are shown in supplementary Table 2. Cancer risks compared with the general population To assess cancer risk in mutation carriers compared with the general population in Israel, the SIRs for all mutation carriers, regardless of their health status at the time of initial counseling were computed. The SIRs were elevated for pancreatic cancer [2.97 (95 %CI 1.83–4.29)] and breast cancer [16.44 (95 % CI 9.65–26.24)]. However, for prostate cancer these rates were 0.59 (95 % CI 0.40–0.84). Given the small number of cancer diagnoses at follow-up in the 210 initially cancer-free participants, formal statistical analyses restricted to that group were not attempted. Cancer incidence within study population Cancer incidence rates in BRCA1/2 carriers combined compared with, non-carrier true negatives revealed no statistically significant differences in cancer incidence or the relative risk, for all cancers (Table 1) as well as specific cancer types (Table 2). However, BRCA2 mutation carriers were more frequently diagnosed with any cancer type compared with BRCA1 mutation carriers (Table 1) both at time of counseling (p = 0.047), and for cancer diagnosed
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after counseling (p = 0.002) and overall (p = 0.0019). Similarly, the relative risk (RR) for developing any cancer type was significantly elevated for BRCA2 mutation carriers compared with BRCA1 mutation carriers: at time of counseling (RR 2.36,1.21–4.58 95 % CI, p = 0.011), after counseling (RR 8.68, 1.92–39.11 95 % CI, p = 0.004), and overall (RR 3.12, 1.87–5.20 95 % CI, p \ 0.0001) (Table 1). Relative risk for specific cancers (Table 2) showed an elevated risk in BRCA2 carriers for prostate cancer (RR 4.54, 1.23–16.68 95 % CI, p = 0.022), a marginal, statistically non-significant risk for breast cancer (RR 6.81, 0.77-60.04 95 % CI, p = 0.083) and no difference in risk for pancreatic cancer (RR 2.13, 0.58–7.72 95 % CI, p = 0.24).
Discussion In the present study, the risk for developing pancreatic and breast cancer in Jewish male BRCA1and BRCA2 mutation carriers was significantly elevated compared with the expected rates in the general population, whereas the risk for developing prostate cancer was not. The results regarding the elevated pancreatic and breast cancer risks in male BRCA mutation carriers are in line with some of the previously published data derived from other, ethnically heterogeneous populations with a more diverse spectrum of germline BRCA1 BRCA2 mutations [2, 7–10]. The current study does not support the putative elevated prostate cancer risk attributed by some previous studies to male BRCA carriers (e.g. [3, 4, 15, 16]). Moreover, there was no overall increased risk for developing other cancer types that were reported among male BRCA carriers in other populations: colon cancer, malignant melanoma, testicular cancer (reviewed by Mahon [17]). The reasons for these seemingly inconsistent results may be attributed to several factors: the short follow-up of the current study, the limited number of participants and cancer diagnosed at follow-up, and the narrow mutational spectrum in the present study or the different study designs of the present study compared with previous reports. The risk for developing pancreatic cancer in female BRCA1 and BRCA2 carriers have also been reported to be elevated compared with non carriers. Thompson and coworkers (9) reported cumulative lifetime risks for female and male BRCA1 carriers: 1,26 (95 % CI 0.92–1.72) and 1.16 (95 % CI 0.83–1,61), respectively, both are statistically insignificant. The Breast cancer linkage consortium (2) reported the cumulative risk for developing pancreatic cancer by the age of 80 years in BRCA2 carriers in females and males—2.3 (95 % CI 1.1–3.5) and 3.2 (95 % CI 1.6–4.9). Mersch and co-workers [18] reported that the SIR for developing pancreatic cancer were elevated for BRCA2
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Table 1 Cancer rate comparisons between BRCA1, BRCA2 mutation carriers, and true negatives
Affected men at time of counseling
BRCA1
BRCA2
Non BRCA
Pv
BRCA1 ? BRCA2
Non BRCA
Pv
RR
13/150
18/88
14/122
0.01
30/240
14/122
0.86
1.09a
1/108
0.0001
0.77
2/137
9/71
5.71
0.74–43.65
0.093
13/150
18/88
0.047
2.36b
1.21–4.58
0.011
Affected men after counseling
2/137
9/71
0.002
8.68b
1.92–39.11
0.004
All affected men
15/150
26/88
1.39a
0.80–2.40
0.24
All affected men
15/150
26/88
0.001
2.95b
1.65–5.26
0.0002
a
41/240
15/122
0.068
0.6–1.8
Affected men after counseling
0.002
1/108
a
Pv
Affected men at time of counseling
15/122
11/208
95 % CI
0.30
Cancers at counseling Cancers at counseling
16/150 16/150
24/88 24/88
16/122
0.013 0.008
40/240
16/122
0.54
1.27 2.55b
0.74–2.17 1.43–4.54
0.38 0.001
Cancers after counseling
2/137
9/71
1/108
0.0001
11/208
1/108
0.068
5.71a
0.74–43.65
0.093
All cancers
18/150
33/88
17/122
0.0002
51/240
17/122
0.15
1.52a
0.92–2.52
0.100
All cancers
18/150
33/88
3.12b
1.87–5.20
\0.0001
0.0005
a
RR calculated for BRCA1 and BRCA2 combined versus Non BRCA
b
RR calculated for BRCA1 versus BRCA2
Table 2 Cancer rate comparisons for prostate, breast, and pancreatic cancer between BRCA1, BRCA2 mutation carriers and true negatives
Prostate
BRCA1
BRCA2
Non BRCA
Pv
BRCA1 ? BRCA2
Non BRCA
Pv
RR
3/150
8/88
3/122
0.022
11/240
3/122
0.40
1.86a
Prostate
3/150
8/88
Breast
1/150
4/88
Breast
1/150
4/88
Pancreas
4/150
5/88
Pancreas
4/150
5/88
0.024 1/122
0.060
5/240
0.66
0.049 2/122
0.254
9/240
0.303
a
RR calculated for BRCA1 and BRCA2 combined versus Non BRCA
b
RR calculated for BRCA1 versus BRCA2
mutation carriers in both males (n = 33) and females (n = 426): males -82.5 (95 % CI 39.5–151.8) and females 13.8 (95 % CI 6.3–26.1). Thus, there is an increased risk for pancreatic cancer in BRCA2 carriers that is gender independent. It is clear that the overall risk for developing cancer is attributable to male BRCA2 mutations more frequently than to BRCA1 mutations. Notably, Moran and co-workers (15) could not show any increased cancer risk for male BRCA1 carriers. Yet, the fact that there are no differences between the rates in conferring pancreatic cancer may signify that both genes are associated with a similar elevated pancreatic cancer risk. One caveat is the fact that some of the analyses included all male carriers, regardless of their health status at counseling, cancer affected and healthy men. However, given the paucity of cancer diagnoses during follow-up, formal statistical analyses were not attempted. The implications of the current study are that elevated pancreatic and breast cancer risks should be conveyed to the
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1/122 2/122
0.34
95 % CI
Pv
0.52–6.55
0.33
b
4.54
1.23–16.68
0.022
2.54a
0.30–21.51
0.39
6.81b
0.77–60.04
0.083
2.28a
0.50–10.42
0.28
2.13b
0.58–7.72
0.24
counseled individuals. Even if confirmed by larger prospective studies, the personal clinical implications to male mutation carriers are limited. There are no studies to support the efficiency and clinical utility of any early detection schemes for male breast cancer. Furthermore, there are no proven efficient methods for early detection of pancreatic cancer. Yet, some centers recommend performing an annual trans-esophageal ultrasound to enhance the possibility of early detection of pancreatic cancer, as suggested by limited studies [19, 20] and an expert opinion [21]. The limitations of this study should be specified: this is a study from a single medical center in Israel, which analyzed cancer types and risks for a small number of BRCA carriers of a limited number of recurring mutations. The small number of carriers and the short follow-up makes detection of rare cancers with moderate penetrance unlikely to be detected. Moreover, since cancer risk is clearly associated with mutation location in breast and ovarian cancer [22] and claims for mutation location effects have
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been made about prostate cancer as well [22], these caveats need to be borne in mind and the results should be interpreted with caution. In conclusion, cancer risk for Jewish male BRCA mutation carriers seems to encompass primarily breast and pancreatic cancer and not prostate cancer. An expansion and validation of these data to other populations seems warranted. Acknowledgments This work was in part funded by a Grant from the Israeli cancer association through the Israeli consortium for inherited cancer. We wish to acknowledge the assistance of the Meirav Comprehensive breast cancer center team at the Sheba Medical Center for assistance in this study. Conflict of interest of interest.
All authors declare that they have no conflicts
Ethical Statement The study was performed after approval by the local IRB (SMC 1492-14) and each participant gave an informed consent.
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