A BRCA1 Splice Site Variant Responsible for Familial Ovarian Cancer in a Han-Chinese Family

Abstract

Objective

Ovarian cancer (OC) is one of the most common and most lethal gynecological malignancies. OC has an age-dependent incidence and occurs more commonly in females older than 50 years old. Most OC patients are diagnosed at an advanced stage and have a poor prognosis. Germline mutations in the BRCA1 DNA repair associated gene (BRCA1) and the BRCA2 DNA repair associated gene (BRCA2) account for 20%–25% of epithelial ovarian cancer (EOC). BRCA1 germline mutations are more common in Chinese EOC patients.

Methods

This study reported a three-generation Han-Chinese family containing four EOC patients and a rectal adenocarcinoma patient. Whole-exome sequencing was performed on two EOC patients and an unaffected individual. Variant validation was also performed in all available members by Sanger sequencing.

Results

A heterozygous splice site variant, c.4358-2A>G in the BRCA1 gene, was identified. Bioinformatic analysis showed that the variant may change the splicing machinery.

Conclusion

The BRCA1 splice site variant, c.4358-2A>G was identified as the likely genetic cause for EOC, and may also be associated with the increased risk of rectal adenocarcinoma in the family. The findings were beneficial for genetic counseling, helpful for cancer prevention in other family members, and may facilitate therapy decision-making in the future to reduce cancer lethality.

Keywords

BRCA1 / splice site variant / whole-exome sequencing / epithelial ovarian cancer

References

[1] TossA, TomaselloC, RazzaboniE, et al.. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int, 2015, 2015: 341723

[2] ManshaM, GillA, ThomsonPC. Potential risk factors of ovarian cancer and analysis of CA125, a biomarker used for its monitoring and diagnosis. Mol Biol Rep, 2019, 46(3): 3325-3332

[3] RoettMA, EvansP. Ovarian cancer: an overview. Am Fam Physician, 2009, 80(6): 609-616

[4] RojasV, HirshfieldKM, GanesanS, et al.. Molecular characterization of epithelial ovarian cancer: implications for diagnosis and treatment. Int J Mol Sci, 2016, 17(12): 2113

[5] NeffRT, SenterL, SalaniR. BRCA mutation in ovarian cancer: testing, implications and treatment considerations. Ther Adv Med Oncol, 2017, 9(8): 519-531

[6] JaysonGC, KohnEC, KitchenerHC, et al.. Ovarian cancer. Lancet, 2014, 384(9951): 1376-1388

[7] RamusSJ, GaytherSA. The contribution of BRCA1 and BRCA2 to ovarian cancer. Mol Oncol, 2009, 3(2): 138-150

[8] DoubeniCA, DoubeniAR, MyersAE. Diagnosis and management of ovarian cancer. Am Fam Physician, 2016, 93(11): 937-944

[9] PooleEM, KonstantinopoulosPA, TerryKL. Prognostic implications of reproductive and lifestyle factors in ovarian cancer. Gynecol Oncol, 2016, 142(3): 574-587

[10] SingerCF, TanYY, MuhrD, et al.. Association between family history, mutation locations, and prevalence of BRCA1 or 2 mutations in ovarian cancer patients. Cancer Med, 2019, 8(4): 1875-1881

[11] EbellMH, CulpMB, RadkeTJ. A systematic review of symptoms for the diagnosis of ovarian cancer. Am J Prev Med, 2016, 50(3): 384-394

[12] HennessyBT, ColemanRL, MarkmanM. Ovarian cancer. Lancet, 2009, 374(9698): 1371-1382

[13] KingMC, MarksJH, MandellJB, et al.. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science, 2003, 302(5645): 643-646

[14] ChenS, ParmigianiG. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol, 2007, 25(11): 1329-1333

[15] OhM, McBrideA, YunS, et al.. BRCA1 and BRCA2 gene mutations and colorectal cancer risk: systematic review and meta-analysis. J Natl Cancer Inst, 2018, 110(11): 1178-1189

[16] SopikV, PhelanC, CybulskiC, et al.. BRCA1 and BRCA2 mutations and the risk for colorectal cancer. Clin Genet, 2015, 87(5): 411-418

[17] HuangX, YuanL, XuH, et al.. Identification of a novel mutation in the ABCA4 gene in a Chinese family with retinitis pigmentosa using exome sequencing. Biosci Rep, 2018, 38(2): BSR20171300

[18] SokolenkoAP, SuspitsinEN, KuliginaES, et al.. Identification of novel hereditary cancer genes by whole exome sequencing. Cancer Lett, 2015, 369(2): 274-288

[19] DengS, WuS, XiaH, et al.. Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome. Biosci Rep, 2020, 40(6): BSR20192510

[20] WuS, GuoY, LiuC, et al.. Identification of a de novo TSC2 variant in a Han-Chinese family with tuberous sclerosis complex. J Chin Med Assoc, 2021, 84(1): 46-50

[21] GuoY, WangP, LiX, et al.. Identifying a BRCA2 c.5722_5723del mutation in a Han-Chinese family with breast cancer. Biosci Rep, 2019, 39(4): BSR20182471

[22] XiangQ, CaoY, XuH, et al.. Identification of novel pathogenic ABCA4 variants in a Han Chinese family with Stargardt disease. Biosci Rep, 2019, 39(1): BSR20180872

[23] LiH, DurbinR. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 2009, 25(14): 1754-1760

[24] RichardsS, AzizN, BaleS, et al.. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med, 2015, 17(5): 405-424

[25] SmithEC. An overview of hereditary breast and ovarian cancer syndrome. J Midwifery Womens Health, 2012, 57(6): 577-584

[26] KennedyRD, QuinnJE, JohnstonPG, et al.. BRCA1: mechanisms of inactivation and implications for management of patients. Lancet, 2002, 360(9338): 1007-1014

[27] ZhuQ, PaoGM, HuynhAM, et al.. BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature, 2011, 477(7363): 179-184

[28] SylvainV, LafargeS, BignonYJ. Dominantnegative activity of a Brca1 truncation mutant: effects on proliferation, tumorigenicity in vivo, and chemosensitivity in a mouse ovarian cancer cell line. Int J Oncol, 2002, 20(4): 845-853

[29] RoyR, ChunJ, PowellSN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer, 2011, 12(1): 68-78

[30] TakaokaM, MikiY. BRCA1 gene: function and deficiency. Int J Clin Oncol, 2018, 23(1): 36-44

[31] ShakyaR, ReidLJ, ReczekCR, et al.. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science, 2011, 334(6055): 525-528

[32] GreenbergRA. BRCA1, everything but the RING?. Science, 2011, 334(6055): 459-460

[33] HawsawiYM, Al-NumairNS, SobahyTM, et al.. The role of BRCA1/2 in hereditary and familial breast and ovarian cancers. Mol Genet Genomic Med, 2019, 7(9): e879

[34] DengCX, BrodieSG. Roles of BRCA1 and its interacting proteins. Bioessays, 2000, 22(8): 728-737

[35] JoualiF, LaarabiFZ, MarchoudiN, et al.. First application of next-generation sequencing in Moroccan breast/ovarian cancer families and report of a novel frameshift mutation of the BRCA1 gene. Oncol Lett, 2016, 12(2): 1192-1196

[36] MuinaoT, PalM, Deka BoruahHP. Origins based clinical and molecular complexities of epithelial ovarian cancer. Int J Biol Macromol, 2018, 118: 1326-1345 Pt A

[37] KossaïM, LearyA, ScoazecJY, et al.. Ovarian cancer: a heterogeneous disease. Pathobiology, 2018, 85(1–2): 41-49

[38] ShiT, WangP, XieC, et al.. BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic-related mutations in BRCA1 associated with an increased risk of ovarian cancer. Int J Cancer, 2017, 140(9): 2051-2059

[39] SmithSA, EastonDF, EvansDG, et al.. Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wild-type chromosome. Nat Genet, 1992, 2(2): 128-131

[40] Meric-BernstamF. Heterogenic loss of BRCA in breast cancer: the “two-hit” hypothesis takes a hit. Ann Surg Oncol, 2007, 14(9): 2428-2429

[41] WernessBA, ParvatiyarP, RamusSJ, et al.. Ovarian carcinoma in situ with germline BRCA1 mutation and loss of heterozygosity at BRCA1 and TP53. J Natl Cancer Inst, 2000, 92(13): 1088-1091

[42] SavageKI, MatchettKB, BarrosEM, et al.. BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability. Cancer Res, 2014, 74(10): 2773-2784

[43] CousineauI, BelmaazaA. BRCA1 haploinsufficiency, but not heterozygosity for a BRCA1-truncating mutation, deregulates homologous recombination. Cell Cycle, 2007, 6(8): 962-971

[44] WidschwendterM, RosenthalAN, PhilpottS, et al.. The sex hormone system in carriers of BRCA1/2 mutations: a case-control study. Lancet Oncol, 2013, 14(12): 1226-1232

[45] KingTA, LiW, BrogiE, et al.. Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis. Ann Surg Oncol, 2007, 14(9): 2510-2518

[46] KonishiH, MohseniM, TamakiA, et al.. Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells. Proc Natl Acad Sci USA, 2011, 108(43): 17773-17778

[47] ZámborszkyJ, SzikrisztB, GervaiJZ, et al.. Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions. Oncogene, 2017, 36(6): 746-755

[48] van der VeldeNM, MouritsMJ, ArtsHJ, et al.. Time to stop ovarian cancer screening in BRCA1/2 mutation carriers?. Int J Cancer, 2009, 124(4): 919-923

[49] BroseMS, RebbeckTR, CalzoneKA, et al.. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst, 2002, 94(18): 1365-1372

[50] KuschelB, LuxMP, GoeckeTO, et al.. Prevention and therapy for BRCA1/2 mutation carriers and women at high risk for breast and ovarian cancer. Eur J Cancer Prev, 2000, 9(3): 139-150