Abstract
Background
Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes.
Methods
Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed.
Results
Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984_3987dupGTCA founder PV; 3 patients had the MSH6 c.3956_3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1–2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36–76 years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines.
Conclusions
This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies.
Similar content being viewed by others
Data availability
All data generated or analyzed during this study were included in this published article.
Abbreviations
- AJ:
-
Ashkenazi Jewish
- CRC:
-
Colorectal cancer
- EC:
-
Endometrial cancer
- GIST:
-
Gastrointestinal stromal tumor
- LOH:
-
Loss of heterozygosity
- HBOC:
-
Hereditary breast and ovarian cancer syndrome
- LS:
-
Lynch syndrome
- MMR:
-
Mismatch repair
- NCCN:
-
National Comprehensive Cancer Network
- NGS:
-
Next-generation sequencing
- PARP:
-
Poly-ADP ribose polymerase
- PV:
-
Pathogenic variant
- RRSO:
-
Risk-reducing salpingo-oophorectomy
References
Kuchenbaecker KB, Hopper JL, Barnes DR et al (2017) Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317:2402–2416. https://doi.org/10.1001/jama.2017.7112
Daly MB, Pilarski R, Yurgelun MB et al (2020) NCCN guidelines insights: genetic/familial high-risk assessment: breast, ovarian and pancreatic, version 1.2020. J Natl Compr Cancer Netw 18:380–391. https://doi.org/10.6004/jnccn.2020.0017
Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA (1999) The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 64:963–970. https://doi.org/10.1086/302320
Satagopan JM, Offit K, Foulkes W, Robson ME, Wacholder S, Eng CM, Karp SE, Begg CBB (2001) The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomark Prev 10:467–473
Moslehi R, Chu W, Karlan B, Fishman D, Risch H, Fields A, Smotkin D, Ben-David Y, Rosenblatt J, Russo D, Schwartz P, Tung N, Warner E, Rosen B, Friedman J, Brunet JS, Narod SA (2000) BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 66:1259–1272. https://doi.org/10.1086/302853
Warner E, Foulkes W, Goodwin P et al (1999) Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91:1241–1247. https://doi.org/10.1093/jnci/91.14.1241
Lavie O, Narod S, Lejbkowicz F, Dishon S, Goldberg Y, Gemer O, Rennert G (2011) Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population. Ann Oncol 22:964–966. https://doi.org/10.1093/annonc/mdq460
Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932. https://doi.org/10.1056/NEJMra012242
Cunningham JM, Kim CY, Christensen ER et al (2001) The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Gene 69:780–790. https://doi.org/10.1086/323658
Bonadona V, Bonaiti B, Olschwang S, French Cancer Genetics Network et al (2011) Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305:2304–2310. https://doi.org/10.1001/jama.2011.743
Møller P, Seppälä TT, Bernstein I, Mallorca Group et al (2018) Cancer risk and survival in path MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut 67:1306–1316. https://doi.org/10.1136/gutjnl-2017-314057
National Comprehensive Cancer Network (2020) Genetic/familial high-risk assessment: colorectal, version 1.2020, NCCN clinical practice guidelines in oncology. https://www.nccn.org/professionals/physician_gls/default.aspx
gnomAD website. Nature Research. https://www.nature.com/collections/afbgiddede/gnomad-website
Foulkes WD, Thiffault I, Gruber SB et al (2002) The founder mutation MSH2*1906G–>C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population. Am J Hum Genet 71:1395–1412. https://doi.org/10.1086/345075
Sun S, Greenwood CM, Thiffault I, Hamel N, Chong G, Foulkes WD (2005) The HNPCC associated MSH2*1906G–>C founder mutation probably originated between 1440 CE and 1715 CE in the Ashkenazi Jewish population. J Med Genet 42:766–768. https://doi.org/10.1136/jmg.2005.030999
Goldberg Y, Porat RM, Kedar I et al (2008) Mutation spectrum in HNPCC in the Israeli population. Fam Cancer 7:309–317. https://doi.org/10.1007/s10689-008-9191-y
Raskin L, Schwenter F, Freytsis M et al (2011) Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome. Clin Genet 79:512–522. https://doi.org/10.1111/j.1399-0004.2010.01594.x
Goldberg Y, Porat RM, Kedar I et al (2010) An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC. Fam Cancer 9:141–150. https://doi.org/10.1007/s10689-009-9298-9
Goldberg Y, Kedar I, Kariiv R et al (2014) Lynch syndrome in high risk Ashkenazi Jews in Israel. Fam Cancer 13:65–73. https://doi.org/10.1007/s10689-013-9675-2
Sopik V, Phelan C, Cybulski C, Narod SA (2015) BRCA1 and BRCA2 mutations and the risk for colorectal cancer. Clin Genet 87:411–418. https://doi.org/10.1111/cge.12497
Thompson D, Easton DF, Breast Cancer Linkage Consortium (2002) Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94:1358–1365. https://doi.org/10.1093/jnci/94.18.1358
Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P (2017) Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523–533. https://doi.org/10.1056/NEJMoa1706450
Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520. https://doi.org/10.1056/NEJMoa1500596
Whitworth J, Skytte A-B, Sunde L, Lim DH, Arends MJ, Happerfield L, Frayling IM, van Minkelen R, Woodward ER, Tischkowitz MD, Maher ER (2016) Multilocus inherited neoplasia alleles syndrome. A case series and review. JAMA Oncol 2:373–379. https://doi.org/10.1001/jamaoncol.2015.4771
Whitworth J, Smith PS, Martin JE et al (2018) Comprehensive cancer-predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes. Am J Hum Genet 103:1–16. https://doi.org/10.1016/j.ajhg.2018.04.013
Stradella A, del Valle J, Rofes P, Feliubadaló L, Grau Garces È, Velasco À, González S, Vargas G, Izquierdo Á, Campos O, Tornero E, Navarro M, Balmaña-Gelpi J, Capellá G, Pineda M, Brunet J, Lázaro C (2019) Does multilocus inherited neoplasia alleles syndrome have severe clinical expression? J Med Genet 56:521–525. https://doi.org/10.1136/jmedgenet-2018-105700
Silva-Smith R, Sussman DA (2018) Co-occurrence of Lynch syndrome and juvenile polyposis syndrome confirmed by multigene panel testing. Fam Cancer 17:87–90. https://doi.org/10.1007/s10689-017-0012-z
Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D’Andrea AD (2002) Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297:606–609. https://doi.org/10.1126/science.1073834
Wimmer K (2008) Etzler J (2008) Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 124:105–122. https://doi.org/10.1007/s00439-008-0542-4
Thiffault I, Hamel N, Pal T et al (2004) Germline truncating mutations in both MSH2 and BRCA2 in a single kindred. Br J Cancer 90:483–491. https://doi.org/10.1038/sj.bjc.6601424
Borg A, Isola J, Chen J, Rubio C, Johansson U, Werelius B, Lindblom A (2000) Germline BRCA1 and HMLH1 mutations in a family with male and female breast carcinoma. Int J Cancer 85:796–800
Kast K, Neuhann TM, Görgens H, Becker K, Keller K, Klink B, Aust D, Distler W, Schröck E, Schackert HK (2012) Germline truncating-mutations in BRCA1 and MSH6 in a patient with early onset endometrial cancer. BMC Cancer 12:531. https://doi.org/10.1186/1471-2407-12-531
Pedroni M, Di Gregorio C, Cortesi L, Reggiani Bonetti L, Magnani G, Simone ML, Medici V, Priore Oliva C, Marino M, de Leon MP (2014) Double heterozygosity for BRCA1 and hMLH1 gene mutations in a 46-year-old woman with five primary tumors. Tech Coloproctol 18:285–289. https://doi.org/10.1007/s10151-013-1030-y
Sorscher S, Ansley K, Delaney SD, Ramkissoon S (2020) The implications of BRCA loss of heterozygosity (LOH) and deficient mismatch repair gene (dMMR) expression in the breast cancer of a patient with both inherited breast and ovarian cancer syndrome (BRCA2) and Lynch syndrome (MLH1). Breast Cancer Res Treat 180:511–514. https://doi.org/10.1007/s10549-020-05569-7
Ferrer-Avargues R, Castillejo MI, Dámaso E et al (2021) Co-occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome. Cancer Commun 41:218–228. https://doi.org/10.1002/cac2.12134
Barnes-Kedar I, Bernstein-Molho R, Ginzach N, Hartmajer S, Shapira T, Magal N, Kalis ML, Peretz T, Shohat M, Basel-Salmon L, Friedman E, Bazak L, Goldberg Y (2018) The yield of full BRCA1/2 genotyping in Israeli high-risk breast/ovarian cancer patients who do not carry the predominant mutations. Breast Cancer Res Treat 172:151–157. https://doi.org/10.1007/s10549-018-4887-7
Win AK, Jenkins MA, Dowty JG, Antoniou AC et al (2017) Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomark Prev 26:404–412. https://doi.org/10.1158/1055-9965.EPI-16-0693
Maxwell KN, Domchek SM, Nathanson KL, Robson ME (2016) Population frequency of germline BRCA1/2 mutations. J Clin Oncol 34:4183–4185. https://doi.org/10.1200/JCO.2016.67.0554
Win AK, Lindor NM, Jenkins MA (2013) Risk of breast cancer in Lynch syndrome: a systematic review. Breast Cancer Res 15:R27–R35. https://doi.org/10.1186/bcr3405
Roberts ME, Jackson SA, Susswein LR et al (2018) MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med 20:1167–1174. https://doi.org/10.1038/gim.2017.254
Espenschied CR, LaDuca H, Li S, McFarland R, Gau CL, Hampel H (2017) Multigene panel testing provides a new perspective on Lynch syndrome. J Clin Oncol 35:2568–2575. https://doi.org/10.1200/JCO.2016.71.9260
Lavie O, Ben-Arie A, Segev Y, Faro J, Barak F, Haya N, Auslender R, Gemer O (2010) BRCA germline mutations in women with uterine serous carcinoma–still a debate. Int J Gynecol Cancer 20:1531–1534. https://doi.org/10.1111/IGC.0b013e3181cd242f
Phelan CM, Iqbal J, Lynch HT, Hereditary Breast Cancer Study Group et al (2014) Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study. Br J Cancer 110:530–534. https://doi.org/10.1038/bjc.2013.741
Oh M, McBride A, Yun S, Bhattacharjee S, Slack M, Martin JR, Jeter J, Abraham I (2018) BRCA1 and BRCA2 gene mutations and colorectal cancer risk: systematic review and meta-analysis. J Natl Cancer Inst 110:1178–1189. https://doi.org/10.1093/jnci/djy148
Waisbren J, Uthe R, Siziopikou K, Kaklaman V (2015) BRCA 1/2 gene mutation and gastrointestinal stromal tumours: a potential association. BMJ Case Rep. https://doi.org/10.1136/bcr-2014-208830
Aronson M, Colas C, Shuen A et al (2021) Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group. J Med Genet. https://doi.org/10.1136/jmedgenet-2020-107627
Yossepowitch O, Olvera N, Satagopan JM, Huang H, Jhanwar S, Rapaport B, Boyd J, Offit K (2003) BRCA1 and BRCA2 germline mutations in lymphoma patients. Leuk Lymphoma 44:127–131. https://doi.org/10.1080/1042819021000040332
Streff H, Profato J, Ye Y, Nebgen D, Peterson SK, Singletary C, Arun BK, Litton JK (2016) Cancer incidence in first- and second-degree relatives of BRCA1 and BRCA2 mutation carriers. Oncologist 21:869–874. https://doi.org/10.1634/theoncologist.2015-0354
Drugs@FDA [database on the Internet]. Silver Spring (MD): U.S. Food and Drug Administration. BLA 125514/S-14 Approval Letter. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/125514Orig1s014ltr.pdf
Lemery S, Keegan P, Pazdur R (2017) First FDA approval agnostic of cancer site-when biomarker defines indication. N Engl J Med 377:1409–1412. https://doi.org/10.1056/NEJMp1709968
US Food and Drug Administration. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-germline-brca-mutated-metastatic-breast-cancer
Moore K, Colombo N, Scambia G et al (2018) Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 379:2495–2505. https://doi.org/10.1056/NEJMoa1810858
Nizialek E, Antonarakis ES (2020) PARP inhibitors in metastatic prostate cancer: evidence to date. Cancer Manag Res 12:8105–8114. https://doi.org/10.2147/CMAR.S227033
Golan T, Hammel P, Reni M et al (2019) Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 381:317–327. https://doi.org/10.1056/NEJMoa1903387
Acknowledgements
We thank Mrs Gloria Ganzach for linguistic editing.
Funding
No funding was procured for this work.
Author information
Authors and Affiliations
Contributions
All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
The study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the local ethics committee.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Laish, I., Friedman, E., Levi-Reznick, G. et al. Double heterozygotes of BRCA1/BRCA2 and mismatch repair gene pathogenic variants: case series and clinical implications. Breast Cancer Res Treat 188, 685–694 (2021). https://doi.org/10.1007/s10549-021-06258-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-021-06258-9