Prevalence and Landscape of Pathogenic or Likely Pathogenic Germline Variants and Their Association With Somatic...

Understanding germline and somatic status in patients with gynecologic cancers could improve risk assessment and guide therapeutic decision-making.

To evaluate the prevalence and landscape of germline pathogenic or likely pathogenic (P/LP) variants and explore whether these variants are associated with somatic phenotypes and cancer risk in unselected patients with gynecologic cancers.

This cross-sectional study retrospectively enrolled unselected patients in China with a gynecologic cancer, including ovarian, cervical, and endometrial, who underwent tumor-normal sequencing using a 520-gene panel from October 1, 2017, through May 31, 2021.

Germline variants in gynecologic cancers.

The P/LP germline variant rates in 62 cancer predisposition genes were assessed using descriptive statistics. The associations of P/LP variant status with age, somatic profiles, and cancer risk were also investigated using the Fisher exact test or Student t test.

A total of 1610 women (median [IQR] age, 54 [47-62] years; 1201 [74.6%] with stage III-IV disease) were included (945 with ovarian cancer, 307 with endometrial cancer, and 358 with cervical cancer). The prevalence of patients with P/LP variants was 20.5% (194 of 945) for ovarian cancer, 13.4% (41 of 307) for endometrial cancer, and 6.4% (23 of 358) for cervical cancer; 95.1% of the germline findings (n = 252) were potentially actionable, mainly in homologous recombination repair (HRR) and mismatch repair genes. Chinese patients with endometrial cancer had a higher rate of P/LP variants than a White population from The Cancer Genome Atlas (42 of 307 [13.7%] vs 24 of 367 [6.5%]; P = .003). In endometrial and cervical cancers, the prevalence of P/LP variants was 12.7% (30 of 237) and 4.8% (13 of 270), respectively, in patients diagnosed at age 45 years or older and increased to 25.0% (9 of 36; P = .09) and 12.0% (10 of 83; P = .04), respectively, for those with an onset age of less than 45 years. Mismatch repair P/LP variants were associated with a younger age at onset for ovarian cancer (46 vs 54 years; P = .02) and endometrial cancer (48 vs 57 years; P < .001), while HRR P/LP variants were associated with a younger age at onset for cervical cancer (46 vs 52 years; P = .04). Carriers of HRR P/LP variants had more prevalent somatic TP53 variants and less common somatic variants in oncogenic driver genes vs noncarriers. BRCA1/2 P/LP variants were also associated with moderate risks for endometrial and cervical cancer.

This study delineates the landscape of germline P/LP variants in Chinese women with gynecologic cancers. The findings highlight the hereditary factor in cervical cancer that has long been neglected and suggest the importance of next-generation sequencing-based genetic testing with a large gene panel for gynecologic cancers.