Double heterozygotes of BRCA1/BRCA2 and mismatch repair gene pathogenic variants: case series and clinical implications.
Ashkenazi Jews
Founder mutations
Hereditary breast and ovarian cancer syndrome
Lynch syndrome
Pathogenic sequence variants
Journal
Breast cancer research and treatment
ISSN: 1573-7217
Titre abrégé: Breast Cancer Res Treat
Pays: Netherlands
ID NLM: 8111104
Informations de publication
Date de publication:
Aug 2021
Aug 2021
Historique:
received:
21
02
2021
accepted:
11
05
2021
pubmed:
5
6
2021
medline:
14
7
2021
entrez:
4
6
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 34086170
doi: 10.1007/s10549-021-06258-9
pii: 10.1007/s10549-021-06258-9
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
BRCA2 Protein
0
BRCA2 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
685-694Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
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
doi: 10.1001/jama.2017.7112
pubmed: 28632866
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
doi: 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
doi: 10.1086/302320
pubmed: 10090881
pmcid: 1377820
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
doi: 10.1086/302853
pubmed: 10739756
pmcid: 1288193
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
doi: 10.1093/jnci/91.14.1241
pubmed: 10413426
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
doi: 10.1093/annonc/mdq460
pubmed: 20924075
Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932. https://doi.org/10.1056/NEJMra012242
doi: 10.1056/NEJMra012242
pubmed: 12621137
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
doi: 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
doi: 10.1001/jama.2011.743
pubmed: 21642682
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
doi: 10.1136/gutjnl-2017-314057
pubmed: 28754778
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
doi: 10.1086/345075
pubmed: 12454801
pmcid: 420003
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
doi: 10.1136/jmg.2005.030999
pubmed: 16199548
pmcid: 1735921
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
doi: 10.1007/s10689-008-9191-y
pubmed: 18389388
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
doi: 10.1111/j.1399-0004.2010.01594.x
pubmed: 21155762
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
doi: 10.1007/s10689-009-9298-9
pubmed: 19851887
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
doi: 10.1007/s10689-013-9675-2
pubmed: 23990280
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
doi: 10.1111/cge.12497
pubmed: 25195694
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
doi: 10.1093/jnci/94.18.1358
pubmed: 12237281
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
doi: 10.1056/NEJMoa1706450
pubmed: 28578601
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
doi: 10.1056/NEJMoa1500596
pubmed: 26028255
pmcid: 4481136
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
doi: 10.1001/jamaoncol.2015.4771
pubmed: 26659639
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
doi: 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
doi: 10.1136/jmedgenet-2018-105700
pubmed: 30580288
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
doi: 10.1007/s10689-017-0012-z
pubmed: 28600700
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
doi: 10.1126/science.1073834
pubmed: 12065746
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
doi: 10.1007/s00439-008-0542-4
pubmed: 18709565
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
doi: 10.1038/sj.bjc.6601424
pubmed: 14735197
pmcid: 2409581
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
doi: 10.1002/(SICI)1097-0215(20000315)85:6<796::AID-IJC10>3.0.CO;2-L
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
doi: 10.1186/1471-2407-12-531
pubmed: 23164213
pmcid: 3537684
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
doi: 10.1007/s10151-013-1030-y
pubmed: 23695190
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
doi: 10.1007/s10549-020-05569-7
pubmed: 32040686
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
doi: 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
doi: 10.1007/s10549-018-4887-7
pubmed: 30014164
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
doi: 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
doi: 10.1200/JCO.2016.67.0554
pubmed: 27551127
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
doi: 10.1186/bcr3405
pubmed: 23510156
pmcid: 3672741
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
doi: 10.1038/gim.2017.254
pubmed: 29345684
pmcid: 6051923
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
doi: 10.1200/JCO.2016.71.9260
pubmed: 28514183
pmcid: 7186580
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
doi: 10.1111/IGC.0b013e3181cd242f
pubmed: 21119368
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
doi: 10.1038/bjc.2013.741
pubmed: 24292448
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
doi: 10.1093/jnci/djy148
pubmed: 30380096
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
doi: 10.1136/bcr-2014-208830
pubmed: 26150619
pmcid: 4493214
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
doi: 10.1136/jmedgenet-2020-107627
pubmed: 33622763
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
doi: 10.1080/1042819021000040332
pubmed: 12691152
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
doi: 10.1634/theoncologist.2015-0354
pubmed: 27306910
pmcid: 4943383
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
doi: 10.1056/NEJMp1709968
pubmed: 29020592
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
doi: 10.1056/NEJMoa1810858
pubmed: 30345884
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
doi: 10.2147/CMAR.S227033
pubmed: 32982407
pmcid: 7489946
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
doi: 10.1056/NEJMoa1903387
pubmed: 31157963
pmcid: 6810605