Comprehensive Germline Genomic Profiling of Patients with Ovarian Cancer: A Cross-Sectional Study

Abstract

Introduction Ovarian cancer is the third most common cancer among Indian women. The data on the hereditary predisposition of these cancers and the clinical outcomes of those with pathogenic mutations is meager in India.

Objective The aim of the current study was to analyze the germline-genetic profile, clinicopathological characteristics, and outcomes of patients with ovarian cancer who were referred for genetic counseling at our Institute.

Materials and Methods It was a cross-sectional observational study. Patients with histological diagnosis of carcinoma ovary at our institute who were referred for genetic counseling from July 2017 to June 2020 were included in the study. All patients underwent pretest counseling. Most patients underwent multigene panel testing with reflex multiplication ligation-dependent probe amplification for large genomic rearrangements, while some received testing for BRCA1 and BRCA2 only. The variants were classified as pathogenic or benign based on American College of Medical Genetics (ACMG) guidelines. Data regarding the demographic profile, clinical characteristics, histopathological findings, family history, treatment received, and outcomes were extracted from the medical record system files.

Results One hundred and one patients were referred to the genetic clinic and underwent genetic counseling. All patients were advised for genetic testing; however, only 72 (71%) underwent testing. A multigene panel testing was done in 51 (70%) patients, and only BRCA1 and BRCA2 genes were tested in 21 (30%). Among the 72 patients who underwent a genetic test, the median age was 47 years (range, 28–82). The most common histopathology was serous (90%), while 85% were diagnosed having stage 3 and 4 ovarian cancer. A pathogenic/likely pathogenic (P/LP) BRCA or non-BRCA mutation was detected in 32 (44%) patients. Six patients (8%) had a variant of unknown significance (VUS). Among P/LP mutations, 85% were in the BRCA gene (75% in BRCA1 and 10% in BRCA2), while 15% were in non-BRCA gene mutations (RAD51, PALB2, MER11, HMMR). Disease-free survival and overall survival were not different in mutation-positive and mutation-negative cohorts.

Conclusions We report 44% P/LP mutations in this selected cohort of patients with carcinoma ovaries. BRCA mutations constituted 85% of all the mutations, while 15% of mutations were in non-BRCA genes.

Keywords

germline - ovarian cancer - BRCA

Ethical Approval

The study protocol was approved by the Institute Ethics Committee vide letter number-IEC-511/5.6.20 RP/50/2020

Consent to Participate

Informed consent was obtained from all patients.

Availability of Data and Material

Data regarding this study will be available from the corresponding author (RP) at reasonable request.

Authors' Contributions

R.P; A.U; S.K; L.K; P.M; M.R; S.D; and S.K contributed to the concept design, patient referrals, and conduct of the study. R.G; D.T; and V.L.R were involved in laboratory testing. A.U; R.P did the statistical analysis.

Publikationsverlauf

Artikel online veröffentlicht:
01. September 2022

• References

• 1 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
• 2 Mathur P, Sathishkumar K, Chaturvedi M. et al; ICMR-NCDIR-NCRP Investigator Group. Cancer Stat 2020: report from national cancer registry programme, India. JCO Glob Oncol 2020; 6: 1063-1075
• 3 Lin JJ, Egorova N, Franco R, Prasad-Hayes M, Bickell NA. Ovarian cancer treatment and survival trends among women older than 65 years of age in the United States, 1995-2008. Obstet Gynecol 2016; 127 (01) 81-89
• 4 Torre LA, Trabert B, DeSantis CE. et al. Ovarian cancer statistics, 2018. CA Cancer J Clin 2018; 68 (04) 284-296
• 5 Walsh T, Casadei S, Lee MK. et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 2011; 108 (44) 18032-18037
• 6 Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007; 25 (11) 1329-1333
• 7 Rebbeck TR, Lynch HT, Neuhausen SL. et al; Prevention and Observation of Surgical End Points Study Group. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002; 346 (21) 1616-1622
• 8 Friedlander M, Moore KN, Colombo N. et al. Patient-centred outcomes and effect of disease progression on health status in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation receiving maintenance olaparib or placebo (SOLO1): a randomised, phase 3 trial. Lancet Oncol 2021; 22 (05) 632-642
• 9 Pujade-Lauraine E, Ledermann JA, Selle F. et al; SOLO2/ENGOT-Ov21 investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017; 18 (09) 1274-1284
• 10 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 11 Singh J, Thota N, Singh S. et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat 2018; 170 (01) 189-196
• 12 Mehta A, Vasudevan S, Sharma SK. et al. Germline BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance associated with breast/ovarian cancer: a report from North India. Cancer Manag Res 2018; 10: 6505-6516
• 13 Gupta S, Rajappa S, Advani S. et al. Prevalence of BRCA1 and BRCA2 mutations among patients with ovarian, primary peritoneal, and fallopian tube cancer in India: a multicenter cross-sectional study. JCO Glob Oncol 2021; Jun;7: 849-861
• 14 Eoh KJ, Kim J, Park HS. et al. Detection of germline mutations in patients with epithelial ovarian cancer using multi-gene panels: beyond BRCA1/2. Cancer Res Treat 2017; •••: 50
• 15 Enomoto T, Aoki D, Hattori K. et al. The first Japanese nationwide multicenter study of BRCA mutation testing in ovarian cancer: CHARacterizing the cross-sectional approach to Ovarian cancer geneTic TEsting of BRCA (CHARLOTTE). Int J Gynecol Cancer 2019; 29 (06) 1043-1049
• 16 Ataseven B, Tripon D, Rhiem K. et al. Prevalence of BRCA1 and BRCA2 mutations in patients with primary ovarian cancer - does the German checklist for detecting the risk of hereditary breast and ovarian cancer adequately depict the need for consultation?. Geburtshilfe Frauenheilkd 2020; 80 (09) 932-940
• 17 Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients | Scientific Reports [Internet]. [cited 2020 Dec 28]. Accessed March 10, 2022 from: https://www.nature.com/articles/srep29506
• 18 Rajkumar T, Meenakumari B, Mani S, Sridevi V, Sundersingh S. Targeted resequencing of 30 genes improves the detection of deleterious mutations in South Indian women with breast and/or ovarian cancers. Asian Pac J Cancer Prev 2015; 16 (13) 5211-5217
• 19 Tassone P, Di Martino MT, Ventura M. et al. Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo. Cancer Biol Ther 2009; 8 (07) 648-653
• 20 Tewari KS, Burger RA, Enserro D. et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. J Clin Oncol 2019; 37 (26) 2317-2328
• 21 Kotsopoulos J, Rosen B, Fan I. et al. Ten-year survival after epithelial ovarian cancer is not associated with BRCA mutation status. Gynecol Oncol 2016; 140 (01) 42-47