Abstract
Germline and somatic mutations of homologous recombination associated genes in non-serous ovarian cancer

Introduction: 
Homologous recombination deficiency (HRD) is a biomarker candidate of PARP inhibitor sensitivity. Although about 50% of high-grade serous (HGS) ovarian carcinoma shows HRD, the prevalence of HRD in non-serous ovarian carcinomas remains unestablished. The aim of this study is to clarify the clinical significance of HRD in non-serous histologic type ovarian carcinomas.

Materials/Patients and methods: 
Targeted sequencing was performed to assess germline and somatic mutations of 16 HR associated genes, 5 ovarian cancer associated genes (TP53, PIK3CA, ARID1A, KRAS, PTEN) and 4 mismatch repair genes in a total of 209 ovarian carcinomas (101 clear cell, 39 endometrioid, 13 mucinous, 6 low-grade serous (LGS), 50 HGS). Possibility for metastatic mucinous carcinoma was excluded by endoscopic examination and CT scanning. Normal DNA derived from peripheral blood cells was used as control. In germline mutation analysis, nonsense, frameshift, and splicing mutations were used. In addition to these mutation types, non-frameshift indel and missense mutations were used in somatic mutation analysis. This retrospective observation study was approved by the institutional review board.

Results: 
101 cases were diagnosed as stage I, and the median age was 57 years old. The distribution of germline and somatic mutations in HR associated genes for each histologic type was shown in the supplementary table. Germline and/or somatic HR gene mutations were detected not only in 23/50 (46%) of HGS, but in 2/6 (33%) LGS, 31/101 (31%) clear cell, 10/39 (26%) endometrioid, and 2/13 (15%) mucinous carcinomas, respectively. Intriguingly, deleterious germline mutations in BRCA2 and CHEK1 were detected in two primary mucinous ovarian carcinomas. Non-serous ovarian carcinomas with somatic mutations in HR associated genes tend to show longer progression free survival compared to those without these mutations (P = 0.06).

Conclusion: 
Our findings demonstrated that PARP inhibitors may give great survival advantage to the patients with non-serous ovarian cancers harboring HR associated gene mutation.