Published online Nov 24, 2019. doi: 10.5306/wjco.v10.i11.358
Peer-review started: March 4, 2019
First decision: April 11, 2019
Revised: August 13, 2019
Accepted: November 4, 2019
Article in press: November 4, 2019
Published online: November 24, 2019
Genetic testing is widely recommended for all patients with epithelial ovarian cancer (EOC) including fallopian tube and primary peritoneal cancers. A 10%-15% incidence of germline BRCA mutations has been reported in unselected EOC patients. However, universal genetic testing in all patients may not be cost-effective if the estimated probability of harboring germline mutations is less than 10%. The incidence of germline mutations may vary across different countries and ethnicities. Different common histologic subtypes in various countries may be significant variables. The high-grade serous subtype is the most common subtype worldwide (approximately 70%), whereas it is less common in Thai EOC patients (rate of only 20%). Per this result, the incidence of germline mutations might be lower in unselected Thai EOC patients.
Different incidences of germline mutations in EOC patients among various countries may guide different recommendations for genetic testing. Universal genetic testing in all EOC patients may not be cost-effective in Thailand. The risk factors associated with the increased likelihood of having germline mutations should be evaluated.
The objective of this study was to evaluate the frequency of germline mutations in EOC patients and to compare the frequency in those with and without clinical risk factors for hereditary ovarian cancer.
This cross-sectional study was conducted on 112 nonmucinous EOC patients including those with fallopian tube and primary peritoneal cancers who underwent primary surgery at our tertiary care hospital between November 2015 and February 2018. Patients were divided into two groups based on clinical risk factors for hereditary ovarian cancer as follows: Age below 40 years, significant family history of cancer, synchronous ovarian and endometrial cancer, and high-grade serous carcinoma (HGSC). All patients who agreed to participate in this study received genetic counseling by a geneticist and provided informed consent. Comprehensive germline mutations were detected using next-generation sequencing.
Germline mutations were detected in 26 of 112 patients (23.2%); 20 patients (17.8%) had BRCA1 or BRCA2 mutations, but 6 patients (5.4%) had mutations in other genes including 1 with an MLH1, 1 with an MSH2, 1 with a RAD51C, 2 with an ATM and 1 with a CDH1 mutation. All mutations were detected in 26 of 82 patients with ≥ 1 risk factor (31.7%), but none were detected in the 30 patients without risk factors (P < 0.001). A significantly higher frequency of germline mutations was found in patients with a significant family history of cancer (56.3% and 10%, P < 0.001). Patients with a significant family history of ovarian cancer had a higher frequency of BRCA mutations than those with a family history of breast cancer (60% and 40.9%, respectively). HGSC was also associated with a higher frequency of germline mutations (40.8% and 9.5%, P < 0.001). Germline BRCA mutations were detected in 38.8% of patients with HGSC but in only 1.6% of those with non-HGSC. Other risk factors such as age below 40 years, personal history of breast cancer, and synchronous ovarian and endometrial cancer were not significantly different in terms of germline mutations (14.3% vs 23.5%, 33.3% vs 21%, 22.2% vs 22.3%, P > 0.05).
A significant family history of cancer and HGSC were the only two significant risk factors associated with a higher frequency of germline mutations. Germline BRCA mutations were detected in 38.8% of patients with HGSC but in only 1.6% of those with non-HGSC. According to the reverse proportion of histologic subtypes in Thai patients, the estimated overall frequency of germline mutations in unselected EOC patients should be only 9.5% overall and only 7.3% for BRCA mutations. These findings suggest the consideration of genetic testing in selected EOC patients in Thailand.
Although universal genetic testing in all EOC patients is recommended by various national professional societies, it may not apply in every country. The narrow availability of genetic testing, the high cost when not reimbursed, and the limited number of geneticists are major obstacles in Thailand. Selected EOC patients should initially be considered for genetic analysis. As the number of patients in this study is still small and since the study was conducted in only one tertiary hospital, it may not fully represent the Thai population. Further prospective studies with multicenter trials should be conducted. The incidence of germline mutations should be studied in unselected EOC Thai patients to identify significant risk factors. Furthermore, BRCA genes should not be the only focus of germline mutation studies, but these studies should also be expanded to include other homologous recombination and MMR genes.