Germline TERT promoter mutations are rare in familial melanoma

TY - JOUR

T1 - Germline TERT promoter mutations are rare in familial melanoma

AU - Harland, Mark

AU - Petljak, Mia

AU - Robles-Espinoza, Carla Daniela

AU - Ding, Zhihao

AU - Gruis, Nelleke A

AU - van Doorn, Remco

AU - Pooley, Karen A

AU - Dunning, Alison M

AU - Aoude, Lauren G

AU - Wadt, Karin Anna Wallentin

AU - Gerdes, Anne-Marie

AU - Brown, Kevin M

AU - Hayward, Nicholas K

AU - Newton-Bishop, Julia A

AU - Adams, David J

AU - Bishop, D Timothy

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.

AB - Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.

U2 - 10.1007/s10689-015-9841-9

DO - 10.1007/s10689-015-9841-9

M3 - Journal article

C2 - 26433962

SN - 1389-9600

VL - 15

SP - 139

EP - 144

JO - Familial Cancer

JF - Familial Cancer

IS - 1

ER -