Frequency of Mutations in Genes Predisposing to Ovarian Cancer in the Czech Population
The authors of a Czech study evaluating the occurrence of mutations in tumor-predisposing genes for ovarian cancer hypothesized that if their occurrence in patients with this diagnosis was significant, identifying carriers of these mutations could help reduce the prevalence and mortality of this disease given the absence of other screening tools.
Introduction
Ovarian cancer is diagnosed in approximately 1000 women in the Czech Republic every year, and around 700 women succumb to this disease annually. The incidence increases with age, peaking between the 6th and 7th decades of life. The hereditary form of ovarian cancer accounts for about 20% of cases. Current clinical recommendations indicate an increased risk of ovarian cancer (relative risk [RR] > 5) in carriers of mutations in 10 genes: BRCA1, BRCA2, BRIP1, EPCAM, MLH1, MSH2, MSH6, RAD51C, RAD51D, and STK11.
Analysis and Findings in the Czech Population
The authors included 1057 women with ovarian cancer (median age 52.6 years) and 617 healthy controls (women over 60 years of age with no personal or family history of malignant tumors) in their analysis. All were examined using the same gene panel via next-generation sequencing on the Illumina platform.
Pathogenic hereditary mutations in genes predisposing to ovarian cancer were found in 30.6% of patients with this tumor. Mutations were found in the BRCA1 gene in 19.9% of cases, in the BRCA2 gene in 7.1%, in the RAD51C, RAD51D, and BRIP1 genes in 1% each, and in genes causing Lynch syndrome (MLH1, MSH2, MSH6) in 0.9%. In the control group, pathogenic mutations in these genes were detected in only 0.7% of women.
The highest incidence of mutations in the examined genes was found in women with both breast and ovarian cancer (59.4%). In solitary ovarian cancer, 24.8% of women had these mutations. Among patients with a positive family history of ovarian cancer, mutations were present in 53.9% of cases and were almost exclusively mutations in the BRCA1/2 genes. Mutations were also detected in 18.2% of patients with a negative family history.
A surprising finding was a 3× higher incidence of mutations in these genes in patients older than 70 years (21.0%) compared to patients aged 30 years or younger (6.7%). The lowest average age at diagnosis was seen in carriers of mutations in the MSH2 gene (42.2 years), followed by mutations in the RAD51C gene (49.2 years), MLH1 (49.9 years), BRCA1 (50.3 years), RAD51D (53.9 years), BRIP1 (54.4 years), BRCA2 (57.6 years), and MSH6 (62.0 years).
Interpretation
Given the limited options for early diagnosis of ovarian cancer, preventive salpingo-oophorectomy (RRSO – risk-reducing salpingo-oophorectomy) is recommended for carriers of mutations in these genes. Because this procedure has numerous side effects, proper timing based on the average age of cancer diagnosis for specific mutations or the age of onset in the family is crucial. The frequency of predisposing mutations found in Czech patients suggests that rationally indicated RRSOs can help reduce the number of deaths from ovarian cancer in the Czech Republic.
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Sources:
1. Soukupová J., Lhotová K., Zemánková P. et al. The contribution of massive parallel sequencing for the diagnosis of hereditary forms of ovarian cancer in the Czech Republic. Klinická onkologie 2019; 32 (Suppl. 2): 2S72–2S78.
2. Institute of Health Information and Statistics of the Czech Republic. Available at: http://uzis.cz
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