Abstract
Purpose :
Familial Uveal Melanomas (FUM), defined as more than one case of uveal melanoma within a family, are rare representing less than 1% of all UM patients. The genetic contribution of UM is still largely unknown. This study was performed to better characterize the clinical phenotype and genetics of FUM.
Methods :
Germline genetic variants were assessed by whole exome sequencing, a 30-gene cancer panel sequencing and/or BAP1 sequencing in a cohort of 43 FUM presented or referred to the Department of Ophthalmology, The Ohio State University. Patients with detectable germline pathogenic/likely pathogenic (P/LP) variants in BAP1 were not tested for other candidate genes. A systematic review of reported FUM was performed.
Results :
Table 1, summarizes the clinical phenotype and genetics of FUM included in the study. Genetic testing of our cohort detected germline BAP1 P/LP variants in 9/43 (21%). Germline P/LP in three established cancer genes (MLH1, PALB2, SMARCE1) were identified in three other families. P/LP variants in five genes possibly associated with cancer predisposition (MMS19, TP53AIP1, DLEC1, RECQL4 and POLI) were identified in five other FUM. Germline P/LP variant in MBD4 was identified in one UM patient with FUM but the variant was not detected in another UM from the family. Except for BAP1, P/LP alteration in other candidate genes were observed in only one patient each. Out of the 121 FUM families reported in the literature, germline testing for BAP1 was carried out on 81 families and P/LP variants were detected in 19%-23%.
Conclusions :
BAP1 is the most important cancer predisposition gene in FUM, detected in 19-23% of families. Germline pathogenic variants in other established or possible cancer predisposition genes are detected in ~21% of FUM. Further assessment of the association of other candidate genes with predisposition to FUM and study of other candidate genes are warranted.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.