MSH2 is the very young onset ovarian cancer predisposition gene, not BRCA1

The genetic cause of very young onset ovarian cancer (VYOC), diagnosed under 30 years of age, is unclear. The histology and underlying genetics in VYOC is significantly different from the overall epithelial ovarian cancer (EOC) population; we aimed to explore this in VYOC cases known to the NorthWest of England. We found mismatch repair genes to be the most commonly affected in VYOCs, especially MSH2. The cumulative likelihood of an EOC in MSH2 heterozygotes is >2% by age 35, with this likelihood still below 0.5% for BRCA1 and rare for BRCA2.


Brief communication
MSH2 is the very young onset ovarian cancer predisposition gene, not BRCA1

Referenced paragraph
The genetic cause of very young onset ovarian cancer (VYOC), diagnosed under 30 years of age, is unclear. 1 The histology and underlying genetics in VYOC is significantly different from the overall epithelial ovarian cancer (EOC) population; we aimed to explore this in VYOC cases known to the North-West of England. We found mismatch repair genes to be the most commonly affected in VYOCs, especially MSH2. The cumulative likelihood of an EOC in MSH2 heterozygotes is >2% by age 35, with this likelihood still below 0.5% for BRCA1 and rare for BRCA2. 2

Article
The inherited landscape of epithelial ovarian cancer (EOC) is well established with contributions from homologous recombination deficiency (HRD) genes, particularly BRCA1 and BRCA2, and mismatch repair deficiency (MMRD) genes MSH2, MLH1, MSH6 and PMS2. 1 Highgrade serous ovarian cancer (HGSOC) is associated with HRD, accounting for up to 23% of HGSOC. 2 Approximately 3% of EOC cases occur in <30 years of age, described as very young onset ovarian cancer (VYOC). 1 The pathology in VYOC differs from overall EOC; a study of 114 VYOC cases found only 28% were serous, while 59% had mucinous pathology. 3 Among the 101 tested cases, no BRCA1 or BRCA2 pathogenic variant (PV) was identified, only 2 MLH1 PVs. 3 VYOC seems associated with MMRD-related EOC as opposed to homologous recombination deficiency (HRD)-related EOC as is seen in BRCA1/2 carriers, in whom the risk of EOC increases from 35 years for BRCA1 carriers and from 45 years in BRCA2 carriers. 2 4 We retrospectively assessed the presence of PVs in VYOC cases aged <30 and 30-34 years before the main risk period is associated with PVs in BRCA1/2. These women had been referred to Manchester Centre for Genomic Medicine (MCGM) within the last two decades following diagnosis with VYOC in the North-West of England. The genetic testing described was performed as part of standard diagnostic testing within MCGM. 5 A series of 77 women with ovarian cancer (9 borderline and 1 granulosa cell tumour in addition to EOCs) were screened for MMRD and HRD germline PVs by sequencing, multiple ligation-dependent probe amplification and a prescreen for MMR immunohistochemistry (IHC) as previously described. 5 We also assessed the proportion of known carriers that developed EOC at age <30 and 30-34 years from our extensive dataset of >4000 female BRCA1/2 carriers and 910 MMRD heterozygotes.
When assessing the proportions of VYOC in PV carriers of HRD and MMRD genes, we included all tested and obligate carriers. There were 2005 female BRCA1, 1999 BRCA2 and 393 MSH2 PV heterozygotes (table 2). One BRCA1 PV carrier (obligate carrier) was identified with an EOC at age <30 (0.05%) (26 years old at diagnosis) but pathology subtype was unavailable. In contrast to the low rate in BRCA1/2 carriers, 4 out of 393 VYOC cases (1%) were found to carry the same MSH2 PV. This proportion was significantly greater in MSH2 PV carriers than either BRCA1 (p=0.003) or BRCA2 (p=0.0007) by χ 2 testing.

Cancer genetics
Very few studies have addressed the contribution of HRD and MMRD genes to VYOC. In addition to the study of 101 cases aged <30, 3 we identified a study of 47 women diagnosed at age ≤40 with EOC who underwent germline screening for 11 genes associated with ovarian cancer. This identified PVs in 13 (28%) of women (BRCA1: 10, BRCA2: 1, MSH2: 1, RAD51D: 1). 6 This study included only two women diagnosed under 30 years of age, neither of whom had an identifiable PV.
Our study has shown that while the genetic predisposition for many early onset ovarian cancers is still unknown, MSH2 is the most important EOC predisposition gene at age <35 years. The cumulative likelihood of an EOC in MSH2 heterozygotes would appear to be >2% by 35, with this likelihood still below 0.5% for BRCA1 and rare for BRCA2 2 ; indeed, two-thirds of cases identified in BRCA2 carriers may not have been driven by HRD. This increased incidence despite the good long-term survival in MSH2 should prompt awareness of the increased risk and consideration for early risk-reduction strategies.