Somatic variants of potential clinical significance in the tumors of phenocopies.

Background: phenocopies are individuals with the same phenotype (i.e. cancer consistent with Hereditary Breast and Ovarian Cancer syndrome = HBOC) as their affected relatives, but not the same genotype as assessed by blood germline testing (i.e. they do not carry a germline or mutation). There is some evidence of increased risk for HBOC-related cancers in relatives of germline variant carriers even though they themselves test negative for the familial variant ( non-carriers). At this time, phenocopies are recommended to undergo the same cancer surveillance as individuals in the general population. This raises the question of whether the increased cancer risk in non-carriers is due to alterations (germline, somatic or epigenetic) in other cancer-associated genes which were not analyzed during analysis.

Methods: To assess the nature and potential clinical significance of somatic variants in phenocopy tumors, DNA from non-carrier tumor tissue was analyzed using next generation sequencing of 572 cancer genes. Tumor diagnoses of the 11 subjects included breast, ovarian, endometrial and primary peritoneal carcinoma. Variants were called using FreeBayes genetic variant detector. Variants were annotated for effect on protein sequence, predicted function, and frequency in different populations from the 1000 genomes project, and presence in variant databases COSMIC and ClinVar using Annovar.

Results: None of the familial mutations were found in the tumor samples tested. The most frequently occurring somatic gene variants were (6/11 cases) and (5/11 cases). somatic variants were found in 2/6 phenocopies, but 0/5 phenocopies. Variants of uncertain significance were found in other DNA repair genes (), one mismatch repair gene (), a DNA demethylation enzyme (), and two histone modifiers ().

Conclusions: Although limited by a small sample size, these results support a role of selected somatic variants and epigenetic mechanisms in the development of tumors in phenocopies.