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Christopher Brian Toomey, Samantha Phou, Kyle Fraser, Mathieu Bakhoum, John A Thorson, Bobby S Korn, Don Osami Kikkawa, Michael Henry Goldbaum, Jonathan H Lin; Frequency of Mismatch Repair Gene Mutations in Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):761.
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© ARVO (1962-2015); The Authors (2016-present)
Uveal melanomas are known to be associated with characteristic genetic changes including mutations in GNAQ, GNA11, BAP1, and SF3B1 as well as chromosomal changes. Germline mutations in mismatch repair genes and microsatellite instability have been implicated in the development of numerous malignant neoplasms such as colon and ovarian cancers. Low frequency microsatellite instability has been reported as an infrequent event in uveal melanomas, yet the frequency of mismatch repair defects in uveal melanomas has yet to be determined. In this study, we reviewed sequencing data and cytogenetic copy number data from uveal melanoma cases to identify the frequency of mutations in mismatch repair genes.
We evaluated uveal melanoma sequencing and cytogenetic copy number data for mutations in six mismatch repair genes: PMS1, PMS2, MSH2, MSH3, MSH6, and MLH1. Data were obtained from next generation sequencing of a panel of cancer-related genes as well as cytogenetic microarray analysis of uveal melanoma cases identified at University of California, San Diego (UCSD). In addition, sequencing and cytogenetic data from uveal melanoma and cutaneous melanoma specimens were examined from The Cancer Genome Atlas (TCGA) database and from uveal melanoma specimens from the Catalogue of Somatic Mutations in Cancer (COSMIC).
Uveal Melanoma:1. PMS1: 1/9 UCSD cases (truncating with premature stop codon); 0/159 COSMIC cases; and 0/80 TCGA cases2. MSH3: 0/9 UCSD cases; 1/115 COSMIC cases (in frame deletion); 0/80 TCGA cases tested for MSH3 mutations3. PMS2: 0/9 UCSD cases; 0/159 COSMIC cases; 0/80 TCGA cases4. MSH2, MSH6, or MLH1: 0/9 UCSD cases; 0/250 COSMIC cases; 0/80 TCGA cases5. Monosomy 3, including the loss of MLH1 (3p22.2), was identified in 3/9 UCSD cases (33%), 39/78 TCGA cases with reported cytogenetic data including chromosome 3p (50%), and 144/179 COSMIC cases with reported cytogenetic data (80.4%).Cutaneous Melanoma:1. PMS1 (20/900; 15/1018), PMS2 (28/900; 26/1018), MSH2 (15/900; 19/1018), MSH3 (27/900; 26/1018), MSH6 (26/900; 12/1018) and/or MLH1 (19/900; 17/1018) were mutated in 13% of cutaneous melanoma TCGA and COSMIC cases
Mutations in mismatch repair genes are rare in uveal melanoma, which are also characterized by a low mutational burden. This is in in contrast to cutaneous melanoma where there is a preponderance of mutations, and mutations in mismatch repair genes are frequent.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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