Hereditary gynaecological cancer syndromes — BRCA and Lynch

A 38-year-old woman sits in your clinic holding a letter: her sister, 42, has just been diagnosed with high-grade serous ovarian cancer, and her mother died of breast cancer at 48. "Am I going to get this?" She is asking the only question that matters, and the answer is no longer vague — it is a number, a gene, and an operation timed to a birthday. This topic teaches you to convert a family story into a pedigree, a score, a test, and a surgical decision. ^[1]

The hereditary syndromes invert the usual order of gynaecological oncology. You are not treating a cancer in front of you; you are preventing a cancer that has not yet formed, in a woman whose genome says it probably will. The skill is identifying her before the cancer does. ^[1]

Overview and definition

Hereditary gynaecological cancer is cancer caused by a germline pathogenic variant — a mutation present in every cell, inherited from a parent, that confers a markedly elevated lifetime risk of one or more tumours. Two syndromes dominate gynaecological practice. ^[1]

Hereditary breast and ovarian cancer (HBOC) is driven by pathogenic variants in the tumour-suppressor genes BRCA1 or BRCA2. The gynaecological phenotype is high-grade serous carcinoma of the ovary, fallopian tube or peritoneum; the breast phenotype dominates the family history. ^[1]

Lynch syndrome (formerly hereditary non-polyposis colorectal cancer, HNPCC) is driven by a defective DNA mismatch repair (MMR) gene — MLH1, MSH2, MSH6, PMS2 or a deletion in EPCAM that silences MSH2. The gynaecological phenotype is endometrial and ovarian cancer; colorectal cancer dominates the family story. ^[6]

The distinction that governs everything: a germline variant is inherited and detectable in blood/saliva, driving cascade testing of relatives; a somatic tumour mutation is acquired in the tumour alone and is not inherited. Only germline variants define a hereditary syndrome. ^[11]

References11ShowHide

1. [1]Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers JAMA, 2017.PMID 28632866
2. [2]Chen S, Parmigiani G Meta-analysis of BRCA1 and BRCA2 penetrance J Clin Oncol, 2007.PMID 17416853
3. [3]Finch AP, Lubinski J, Møller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation J Clin Oncol, 2014.PMID 24567435
4. [4]Domchek SM, Friebel TM, Neuhausen SL, et al. Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study Lancet Oncol, 2006.PMID 16510331
5. [5]Evans DG, Eccles DM, Rahman N, et al. A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO J Med Genet, 2004.PMID 15173236
6. [6]Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome JAMA, 2011.PMID 21642682
7. [7]Møller P, Seppälä T, Bernstein I, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database Gut, 2017.PMID 26657901
8. [8]Kurman RJ, Shih IeM The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory Am J Surg Pathol, 2010.PMID 20154587
9. [9]Medeiros F, Muto MG, Lee Y, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome Am J Surg Pathol, 2006.PMID 16434898
10. [10]Stanciu PI, Ind TEJ, Barton DPJ, et al. Development of peritoneal carcinoma in women diagnosed with serous tubal intraepithelial carcinoma (STIC) following risk-reducing salpingo-oophorectomy (RRSO) J Ovarian Res, 2019.PMID 31128592
11. [11]Sabiani L, Barrou J, Mathis J, Eisinger F How to manage BRCA mutation carriers? Horm Mol Biol Clin Investig, 2020.PMID 32459193