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. 2014 Dec 13;107(2):dju408.
doi: 10.1093/jnci/dju408. Print 2015 Feb.

Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma

Lauren G Aoude  1 , Antonia L Pritchard  1 , Carla Daniela Robles-Espinoza  1 , Karin Wadt  1 , Mark Harland  1 , Jiyeon Choi  1 , Michael Gartside  1 , Víctor Quesada  1 , Peter Johansson  1 , Jane M Palmer  1 , Andrew J Ramsay  1 , Xijun Zhang  1 , Kristine Jones  1 , Judith Symmons  1 , Elizabeth A Holland  1 , Helen Schmid  1 , Vanessa Bonazzi  1 , Susan Woods  1 , Ken Dutton-Regester  1 , Mitchell S Stark  1 , Helen Snowden  1 , Remco van Doorn  1 , Grant W Montgomery  1 , Nicholas G Martin  1 , Thomas M Keane  1 , Carlos López-Otín  1 , Anne-Marie Gerdes  1 , Håkan Olsson  1 , Christian Ingvar  1 , Ake Borg  1 , Nelleke A Gruis  1 , Jeffrey M Trent  1 , Göran Jönsson  1 , D Timothy Bishop  1 , Graham J Mann  1 , Julia A Newton-Bishop  1 , Kevin M Brown  1 , David J Adams  1 , Nicholas K Hayward  1
Affiliations

Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma

Lauren G Aoude et al. J Natl Cancer Inst. .

Abstract

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.

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Figures

Figure 1.
Figure 1.
Mutations in ACD and TERF2IP that segregate with melanoma. The age at first diagnosis of cutaneous malignant melanoma (CMM) is indicated in brackets. If the individual has had more than one primary melanoma, the first age at onset is annotated and the total number of CMMs is given. A line through a symbol indicates that the individual is deceased. Individuals carrying a mutation are indicated by “M,” while family members that are wild-type for the indicated variant are annotated “WT.” “(M)” indicates an individual is an obligate carrier. Square symbols indicate males and circles females. Black symbols represent confirmed CMM case patients and gray symbols unconfirmed case patients. Symbols with a central black circle represent individuals with a confirmed cancer other than CMM. Those family members with other unconfirmed cancers are indicated by symbols containing a central gray circle. Unaffected siblings are indicated by a diamond with the number of siblings shown in the center of the symbol. ACD = adrenocortical dysplasia protein homolog; TERF2IP = telomeric repeat binding factor 2 interacting protein.
Figure 2.
Figure 2.
Relative location of germline variants in melanoma case patients with respect to adrenocortical dysplasia protein homolog (ACD) and TERF2IP protein domains (A) and conservation of ACD and TERF2IP variants in melanoma families across placental mammals (B) and spanning species clades (C). ACD = adrenocortical dysplasia protein homolog; TERF2IP = telomeric repeat binding factor 2 interacting protein.
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