Predicting the likelihood of a pathogenic variant being somatic by testing only tumour DNA in non-mucinous high-grade epithelial ovarian cancer.

Aims: Clinical guidelines recommend testing both germline and tumour DNA for pathogenic variants (PVs) in non-mucinous high-grade epithelial ovarian cancer (NMEOC). In this study, we show that some tumour PVs are highly likely to be somatic based on certain clinical and variant characteristics, meaning it may not be necessary to test all NMEOC cases for germline PVs.

Methods: An observational study that included all tumour PVs detected in cases of NMEOC in the Northwest of England between July 2017 and February 2022. All tumour PVs were compared with PVs recorded in a prospectively gathered pan-cancer germline (g) testing database for the same geographical region (g PVs=910 and g PVs=922). Tumour PVs were categorised as common (≥1%), uncommon (<1%) or absent from the germline database.

Results: One hundred and thirteen tumour PVs were detected in 111 NMEOC cases. There were 69 germline and 44 somatic variants. The mean age at diagnosis for g and somatic (s) PVs was 56.9 and 68.5 years, respectively (Student's t-test p<0.0001). All s PVs were detected in non-familial cases. All tumour PVs with a variant allele frequency (VAF) <35% in non-familial cases were somatic variants. Eighty-one per cent of germline-tumour PVs were present (common=31, uncommon=25) in the g testing database, while 89% of somatic-tumour PVs were absent (n=39).

Conclusions: We predict the likelihood of a tumour PV being somatic is 99.8% in non-familial cases of NMEOC diagnosed aged ≥75, where the VAF is ≤30% and there is no regional germline commonality.