Aoude, Lauren G2; Pritchard, Antonia L2; Robles-Espinoza, Carla Daniela2; Wadt, Karin2; Harland, Mark2; Choi, Jiyeon2; Gartside, Michael2; Quesada, Víctor2; Johansson, Peter2; Palmer, Jane M2; Ramsay, Andrew J2; Zhang, Xijun2; Jones, Kristine2; Symmons, Judith2; Holland, Elizabeth A2; Schmid, Helen2; Bonazzi, Vanessa2; Woods, Susan2; Dutton-Regester, Ken2; Stark, Mitchell S2; Snowden, Helen2; van Doorn, Remco2; Montgomery, Grant W2; Martin, Nicholas G2; Keane, Thomas M2; López-Otín, Carlos2; Gerdes, Anne-Marie3; Olsson, Håkan2; Ingvar, Christian2; Borg, Ake2; Gruis, Nelleke A2; Trent, Jeffrey M2; Jönsson, Göran2; Bishop, D Timothy2; Mann, Graham J2; Newton-Bishop, Julia A2; Brown, Kevin M2; Adams, David J2; Hayward, Nicholas K2
1 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 unknown3 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
BACKGROUND: The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families. METHODS: Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction). RESULTS: Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma. CONCLUSIONS: Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.
Jnci - Journal of the National Cancer Institute, 2015, Vol 107, Issue 2, p. 1-7