Craig C Teerlink1, Chad Huff2, Jeff Stevens1, Yao Yu2, Sheri L Holmen3,4, Mark R Silvis3, Kirby Trombetti3, Hua Zhao2, Douglas Grossman3,5, James M Farnham1, Jingran Wen6, Julio C Facelli7, Alun Thomas1, Markus Babst8,9, Scott R Florell5, Laurence Meyer5,10, John J Zone5, Sancy Leachman11, Lisa A Cannon-Albright1,3. 1. Genetic Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT. 2. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX. 3. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT. 4. Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT. 5. Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT. 6. Utah Department of Health, Salt Lake City, UT. 7. Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT. 8. Center for Cell and Genome Science, University of Utah, Salt Lake City, UT. 9. Department of Biology, University of Utah, Salt Lake City, UT. 10. George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT. 11. Department of Dermatology and Knight Cancer Institute, Oregon Health and Science University, Portland, OR.
Abstract
Background: Statistically significant linkage of melanoma to chromosome 9q21 was previously reported in a Danish pedigree resource and independently confirmed in Utah high-risk pedigrees, indicating strong evidence that this region contains a melanoma predisposition gene. Methods: Whole-exome sequencing of pairs of related melanoma case subjects from two pedigrees with evidence of 9q21 linkage was performed to identify the responsible predisposition gene. Candidate variants were tested for association with melanoma in an independent set of 454 unrelated familial melanoma case subjects and 396 unrelated cancer-free control subjects from Utah, and 1534 melanoma case subjects and 1146 noncancer control subjects from Texas (MD Anderson) via a two-sided Fisher exact test. Results: A rare nonsynonymous variant in Golgi Membrane Protein 1 (GOLM1), rs149739829, shared in two hypothesized predisposition carriers in one linked pedigree was observed. Segregation of this variant in additional affected relatives of the index carriers was confirmed. A statistically significant excess of carriers of the variant was observed among Utah case subjects and control subjects (odds ratio [OR] = 9.81, 95% confidence interval [CI] = 8.35 to 11.26, P < .001) and statistically significantly confirmed in Texas case subjects and control subjects (OR = 2.45, 95% CI = 1.65 to 3.25, P = .02). Conclusion: These findings support GOLM1 as a candidate melanoma predisposition gene.
Background: Statistically significant linkage of melanoma to chromosome 9q21 was previously reported in a Danish pedigree resource and independently confirmed in Utah high-risk pedigrees, indicating strong evidence that this region contains a melanoma predisposition gene. Methods: Whole-exome sequencing of pairs of related melanoma case subjects from two pedigrees with evidence of 9q21 linkage was performed to identify the responsible predisposition gene. Candidate variants were tested for association with melanoma in an independent set of 454 unrelated familial melanoma case subjects and 396 unrelated cancer-free control subjects from Utah, and 1534 melanoma case subjects and 1146 noncancer control subjects from Texas (MD Anderson) via a two-sided Fisher exact test. Results: A rare nonsynonymous variant in Golgi Membrane Protein 1 (GOLM1), rs149739829, shared in two hypothesized predisposition carriers in one linked pedigree was observed. Segregation of this variant in additional affected relatives of the index carriers was confirmed. A statistically significant excess of carriers of the variant was observed among Utah case subjects and control subjects (odds ratio [OR] = 9.81, 95% confidence interval [CI] = 8.35 to 11.26, P < .001) and statistically significantly confirmed in Texas case subjects and control subjects (OR = 2.45, 95% CI = 1.65 to 3.25, P = .02). Conclusion: These findings support GOLM1 as a candidate melanoma predisposition gene.
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