Purchase this article with an account.
Mohamed H Abdel-Rahman, Klarke M Sample, Timothy Grosel, Ben Kelly, David Gordon, Maciej Pietrzak, Robert Pilarski, Frederick Davidorf, Peter White, Colleen M Cebulla; Exploratory study of candidate genes other than BAP1 associated with hereditary predisposition to uveal melanoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):958.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
About 12% of uveal melanoma (UM) patients have features suggestive of hereditary cancer predisposition. Germline mutation in BAP1 and BRCA2 explains only a small subset of these patients suggesting the existence of other candidate genes. The aim of this study was to identify other candidate genes associated with hereditary predisposition to UM.
Whole exome sequencing of 28 probands with no detectable mutation in BAP1. Probands included 24 with familial UM, one with bilateral UM, one with congenital UM and 2 patients with strong family history of cancers observed in the BAP1-TPDS. Validation of variants was carried out by direct sequencing. Functional validation was carried out by combination of genomic and proteomic studies. Germline alterations in the 80 UM reported in The Cancer Genome Atlas Project (TCGA) was also assessed.
We identified coding pathogenic or potentially pathogenic variants in 5 cancer predisposition genes (CHEK2, MLH1, PALB2, SMARCE1, and RET) in 5 patients. Biallelic inactivation of PALB2 and MLH1 were observed in the tumors from the respective patients. No evidence of biallelic inactivation of CHEK2 or SMARCE1 was observed in the tumors. Variants in cancer associated genes, mostly missense variants of uncertain significance, were identified in 24/29 patients. Several of these variants were in genes in the DNA damage repair pathway. TCGA data revealed one patient with germline pathogenic mutation in BAP1 and several with pathogenic variants of other DNA repair genes.
The study provides limited/moderate evidence of gene/disease association of germline mutation in PALB2 and MLH1 with hereditary predisposition to UM. It also identifies several other potential candidate genes. The results suggest locus heterogeneity in predisposition to UM and potential multi-genic etiology in a subset of patients. Alterations in genes in the DNA damage repair pathway is important in patients with hereditary predisposition to UM and in some with sporadic UM. Validation in a larger UM cohort is warranted.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
This PDF is available to Subscribers Only