July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Frequency of Mismatch Repair Gene Mutations in Uveal Melanoma
Author Affiliations & Notes
  • Christopher Brian Toomey
    Shiley Eye Insitute, UC, San Diego, San Diego, California, United States
  • Samantha Phou
    Pathology, University of California, San Diego, La Jolla, California, United States
  • Kyle Fraser
    Pathology, University of California, San Diego, La Jolla, California, United States
  • Mathieu Bakhoum
    Shiley Eye Insitute, UC, San Diego, San Diego, California, United States
  • John A Thorson
    Pathology, University of California, San Diego, La Jolla, California, United States
  • Bobby S Korn
    Shiley Eye Insitute, UC, San Diego, San Diego, California, United States
  • Don Osami Kikkawa
    Shiley Eye Insitute, UC, San Diego, San Diego, California, United States
  • Michael Henry Goldbaum
    Shiley Eye Insitute, UC, San Diego, San Diego, California, United States
  • Jonathan H Lin
    Pathology, University of California, San Diego, La Jolla, California, United States
    Shiley Eye Insitute, UC, San Diego, San Diego, California, United States
  • Footnotes
    Commercial Relationships   Christopher Toomey, None; Samantha Phou, None; Kyle Fraser, None; Mathieu Bakhoum, None; John Thorson, None; Bobby Korn, None; Don Kikkawa, None; Michael Goldbaum, None; Jonathan Lin, None
  • Footnotes
    Support  NIH Grant P30EY022589
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 761. doi:https://doi.org/
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    • Get Citation

      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. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : 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.

Methods : 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).

Results :
Uveal Melanoma:
1. PMS1: 1/9 UCSD cases (truncating with premature stop codon); 0/159 COSMIC cases; and 0/80 TCGA cases
2. MSH3: 0/9 UCSD cases; 1/115 COSMIC cases (in frame deletion); 0/80 TCGA cases tested for MSH3 mutations
3. PMS2: 0/9 UCSD cases; 0/159 COSMIC cases; 0/80 TCGA cases
4. MSH2, MSH6, or MLH1: 0/9 UCSD cases; 0/250 COSMIC cases; 0/80 TCGA cases
5. 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

Conclusions : 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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