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

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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.

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References

  1. Toss A, Tomasello C, Razzaboni E, et al. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int, 2015,2015:341723

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Mansha M, Gill A, Thomson PC. 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

    Article  CAS  PubMed  Google Scholar 

  3. Roett MA, Evans P. Ovarian cancer: an overview. Am Fam Physician, 2009,80(6):609–616

    PubMed  Google Scholar 

  4. Rojas V, Hirshfield KM, Ganesan S, et al. Molecular characterization of epithelial ovarian cancer: implications for diagnosis and treatment. Int J Mol Sci, 2016,17(12): 2113

    Article  PubMed Central  CAS  Google Scholar 

  5. Neff RT, Senter L, Salani R. BRCA mutation in ovarian cancer: testing, implications and treatment considerations. Ther Adv Med Oncol, 2017,9(8):519–531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jayson GC, Kohn EC, Kitchener HC, et al. Ovarian cancer. Lancet, 2014,384(9951):1376–1388

    Article  PubMed  Google Scholar 

  7. Ramus SJ, Gayther SA. The contribution of BRCA1 and BRCA2 to ovarian cancer. Mol Oncol, 2009,3(2):138–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Doubeni CA, Doubeni AR, Myers AE. Diagnosis and management of ovarian cancer. Am Fam Physician, 2016,93(11):937–944

    PubMed  Google Scholar 

  9. Poole EM, Konstantinopoulos PA, Terry KL. Prognostic implications of reproductive and lifestyle factors in ovarian cancer. Gynecol Oncol, 2016,142(3):574–587

    Article  PubMed  Google Scholar 

  10. Singer CF, Tan YY, Muhr D, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ebell MH, Culp MB, Radke TJ. A systematic review of symptoms for the diagnosis of ovarian cancer. Am J Prev Med, 2016,50(3):384–394

    Article  PubMed  Google Scholar 

  12. Hennessy BT, Coleman RL, Markman M. Ovarian cancer. Lancet, 2009,374(9698):1371–1382

    Article  CAS  PubMed  Google Scholar 

  13. King MC, Marks JH, Mandell JB, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science, 2003,302(5645):643–646

    Article  CAS  PubMed  Google Scholar 

  14. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol, 2007,25(11):1329–1333

    Article  PubMed  Google Scholar 

  15. Oh M, McBride A, Yun S, 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

    Article  PubMed  CAS  Google Scholar 

  16. Sopik V, Phelan C, Cybulski C, et al. BRCA1 and BRCA2 mutations and the risk for colorectal cancer. Clin Genet, 2015,87(5):411–418

    Article  CAS  PubMed  Google Scholar 

  17. Huang X, Yuan L, Xu H, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sokolenko AP, Suspitsin EN, Kuligina ES, et al. Identification of novel hereditary cancer genes by whole exome sequencing. Cancer Lett, 2015,369(2):274–288

    Article  CAS  PubMed  Google Scholar 

  19. Deng S, Wu S, Xia H, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wu S, Guo Y, Liu C, 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

    Article  CAS  PubMed  Google Scholar 

  21. Guo Y, Wang P, Li X, et al. Identifying a BRCA2 c.5722_5723del mutation in a Han-Chinese family with breast cancer. Biosci Rep, 2019,39(4):BSR20182471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Xiang Q, Cao Y, Xu H, et al. Identification of novel pathogenic ABCA4 variants in a Han Chinese family with Stargardt disease. Biosci Rep, 2019,39(1): BSR20180872

    Article  PubMed  PubMed Central  Google Scholar 

  23. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 2009, 25(14):1754–1760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Richards S, Aziz N, Bale S, 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

    Article  PubMed  PubMed Central  Google Scholar 

  25. Smith EC. An overview of hereditary breast and ovarian cancer syndrome. J Midwifery Womens Health, 2012,57(6):577–584

    Article  PubMed  Google Scholar 

  26. Kennedy RD, Quinn JE, Johnston PG, et al. BRCA1: mechanisms of inactivation and implications for management of patients. Lancet, 2002,360(9338):1007–1014

    Article  CAS  PubMed  Google Scholar 

  27. Zhu Q, Pao GM, Huynh AM, et al. BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature, 2011,477(7363):179–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sylvain V, Lafarge S, Bignon YJ. 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

    CAS  PubMed  Google Scholar 

  29. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer, 2011,12(1):68–78

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Takaoka M, Miki Y. BRCA1 gene: function and deficiency. Int J Clin Oncol, 2018,23(1):36–44

    Article  CAS  PubMed  Google Scholar 

  31. Shakya R, Reid LJ, Reczek CR, et al. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science, 2011,334(6055): 525–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Greenberg RA. BRCA1, everything but the RING? Science, 2011,334(6055):459–460

    Article  CAS  PubMed  Google Scholar 

  33. Hawsawi YM, Al-Numair NS, Sobahy TM, et al. The role of BRCA1/2 in hereditary and familial breast and ovarian cancers. Mol Genet Genomic Med, 2019,7(9): e879

    Article  PubMed  PubMed Central  Google Scholar 

  34. Deng CX, Brodie SG. Roles of BRCA1 and its interacting proteins. Bioessays, 2000,22(8):728–737

    Article  CAS  PubMed  Google Scholar 

  35. Jouali F, Laarabi FZ, Marchoudi N, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Muinao T, Pal M, Deka Boruah HP. Origins based clinical and molecular complexities of epithelial ovarian cancer. Int J Biol Macromol, 2018,118(Pt A):1326–1345

    Article  CAS  PubMed  Google Scholar 

  37. Kossaï M, Leary A, Scoazec JY, et al. Ovarian cancer: a heterogeneous disease. Pathobiology, 2018,85(1–2):41–49

    Article  PubMed  Google Scholar 

  38. Shi T, Wang P, Xie C, 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

    Article  CAS  PubMed  Google Scholar 

  39. Smith SA, Easton DF, Evans DG, 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  41. Werness BA, Parvatiyar P, Ramus SJ, 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

    Article  CAS  PubMed  Google Scholar 

  42. Savage KI, Matchett KB, Barros EM, et al. BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability. Cancer Res, 2014,74(10):2773–2784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cousineau I, Belmaaza A. BRCA1 haploinsufficiency, but not heterozygosity for a BRCA1-truncating mutation, deregulates homologous recombination. Cell Cycle, 2007,6(8):962–971

    Article  CAS  PubMed  Google Scholar 

  44. Widschwendter M, Rosenthal AN, Philpott S, et al. The sex hormone system in carriers of BRCA1/2 mutations: a case-control study. Lancet Oncol, 2013,14(12):1226–1232

    Article  CAS  PubMed  Google Scholar 

  45. King TA, Li W, Brogi E, et al. Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis. Ann Surg Oncol, 2007,14(9):2510–2518

    Article  PubMed  Google Scholar 

  46. Konishi H, Mohseni M, Tamaki A, 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zámborszky J, Szikriszt B, Gervai JZ, 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

    Article  PubMed  CAS  Google Scholar 

  48. van der Velde NM, Mourits MJ, Arts HJ, et al. Time to stop ovarian cancer screening in BRCA1/2 mutation carriers? Int J Cancer, 2009,124(4):919–923

    Article  CAS  PubMed  Google Scholar 

  49. Brose MS, Rebbeck TR, Calzone KA, et al. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst, 2002, 94(18):1365–1372

    Article  CAS  PubMed  Google Scholar 

  50. Kuschel B, Lux MP, Goecke TO, 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

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, 410013, China

    Peng-zhi Hu, Xiang-yu Chen, Zhi-jian Yang, Hao Deng & La-mei Yuan

  2. Department of Radiology, the Third Xiangya Hospital, Central South University, Changsha, 410013, China

    Peng-zhi Hu

  3. Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, China

    Wei Xiong

  4. Department of Gastrointestinal Surgery, the Third Xiangya Hospital, Central South University, Changsha, 410013, China

    Xiao-rong Li

  5. Department of Pathology, the Third Xiangya Hospital, Central South University, Changsha, 410013, China

    Wen-zhi Deng

  6. Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, 410013, China

    Li-na Gong & Hao Deng

  7. Disease Genome Research Center, Central South University, Changsha, 410013, China

    Hao Deng

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  1. Peng-zhi Hu
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  9. La-mei Yuan
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Corresponding author

Correspondence to La-mei Yuan.

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Conflict of Interest Statement

The authors declare that there is no conflict of interest with any financial organization, corporation or individual that can inappropriately influence this work.

This project was supported by grants from the National Natural Science Foundation of China (No. 81800219 and No. 81873686), Natural Science Foundation of Hunan Province (No. 2019JJ50927, No. 2020JJ3057 and No. 2020JJ4830), the Lotus Scholars Program of Hunan Province, and the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University (No. YX202109).

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Hu, Pz., Chen, Xy., Xiong, W. et al. A BRCA1 Splice Site Variant Responsible for Familial Ovarian Cancer in a Han-Chinese Family. CURR MED SCI 42, 666–672 (2022). https://doi.org/10.1007/s11596-022-2527-2

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  • DOI: https://doi.org/10.1007/s11596-022-2527-2

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