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

Lela Buckingham,Jacob Rotmensch,Vincent Hong Hu,Melody Cobleigh,Lydia Usha,Mark Maienschein-Cline,Stefan Green,Rachel Mitchell,Kelly Burgess

doi:10.1186/s13053-019-0117-5

Abstract

BackgroundBRCA 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 BRCA1 or BRCA2 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 (BRCA non-carriers). At this time, BRCA 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 BRCA non-carriers is due to alterations (germline, somatic or epigenetic) in other cancer-associated genes which were not analyzed during BRCA analysis.MethodsTo assess the nature and potential clinical significance of somatic variants in BRCA phenocopy tumors, DNA from BRCA 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.ResultsNone of the familial BRCA1/2 mutations were found in the tumor samples tested. The most frequently occurring somatic gene variants were ROS1(6/11 cases) and NUP98 (5/11 cases). BRCA2 somatic variants were found in 2/6 BRCA1 phenocopies, but 0/5 BRCA2 phenocopies. Variants of uncertain significance were found in other DNA repair genes (ERCC1, ERCC3, ERCC4, FANCD2, PALB2), one mismatch repair gene (PMS2), a DNA demethylation enzyme (TET2), and two histone modifiers (EZH2, SUZ12).ConclusionsAlthough limited by a small sample size, these results support a role of selected somatic variants and epigenetic mechanisms in the development of tumors in BRCA phenocopies.

Highlights

Cancer predisposition in hereditary breast and ovarian cancer (HBOC) syndrome is caused by pathogenic germline variants in the BRCA1/2 genes and is inherited in an autosomal dominant pattern
Some authors argue that their cancer risk is the same as in the general population [24, 42], some conclude that their risk is the same as high risk families without identified germline BRCA pathogenic variants [20], but, overall, most authors agree that the risk is increased with a breast cancer risk ratio (RR) of up to 5.1 [14, 27, 32, 35]
The current study addresses the origin of a disease phenocopy, an HBOC syndrome, in the absence of a familial gene pathogenic variant

Summary

Introduction

Cancer predisposition in hereditary breast and ovarian cancer (HBOC) syndrome is caused by pathogenic germline variants in the BRCA1/2 genes (germline BRCA variants) and is inherited in an autosomal dominant pattern. BRCA 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 BRCA1 or BRCA2 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 (BRCA non-carriers) At this time, BRCA phenocopies are recommended to undergo the same cancer surveillance as individuals in the general population. BRCA 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 BRCA non-carriers is due to alterations (germline, somatic or epigenetic) in other cancerassociated genes which were not analyzed during BRCA analysis

Methods

Results

Discussion

Conclusion