Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Abstract

TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10 −7 ), reduced estrogen receptor negative (ER-negative) (P=1.0×10 −8 ) and BRCA1 mutation carrier (P=1.1×10 −5 ) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10 −14 ), increased low malignant potential ovarian cancer risk (P=1.3×10 −15 ) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10 −12 ) and BRCA1 mutation carrier (P=1.6×10 −14 ) breast and invasive ovarian (P=1.3×10 −11 ) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splicevariant.

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

“…2,[5][6][7][8][9][10][11] The genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) gene regions could play a role in MM etiology for two reasons: first the two genes are responsible for crucial cellular processes, namely telomere homeostasis, second their polymorphic variants have been found to be associated with multiple cancer types and other human phenotypes. [12][13][14][15][16][17][18][19][20][21][22][23][24] TERT and TERC constitute the telomerase complex, 25 whose correct functioning is fundamental for the accurate de novo synthesis of telomeric ends. Even moderate changes in TERT and TERC activity could profoundly affect telomere homeostasis.…”

“…30 It is not, therefore, surprising that it harbors multiple variants associated with risk of different diseases and in particular with various cancer types. For example the rs2736100 SNP is associated with glioma, testicular and lung cancer, 16,18,20 while rs401681 is associated with lung, bladder and pancreatic cancer, 17,19,21 rs10069690 with estrogen receptor-negative breast cancer 12,13 and rs2242652 with breast, prostate and ovarian cancer. 12,14,15 In addition, TERT polymorphisms are associated with other human phenotypes such as pulmonary fibrosis and PSA levels.…”

“…For example the rs2736100 SNP is associated with glioma, testicular and lung cancer, 16,18,20 while rs401681 is associated with lung, bladder and pancreatic cancer, 17,19,21 rs10069690 with estrogen receptor-negative breast cancer 12,13 and rs2242652 with breast, prostate and ovarian cancer. 12,14,15 In addition, TERT polymorphisms are associated with other human phenotypes such as pulmonary fibrosis and PSA levels. [22][23][24]34 A very recent GWAS has reported the association of rs10936599 with increased risk of MM.…”

Low frequency of TERT promoter somatic mutation in 313 sporadic esophageal squamous cell carcinomas

“…1 Recently point mutations in the promoter of TERT gene have been shown to occur in melanomas, gliomas and other tumors and the mutation increased telomerase expression. [2][3][4] Esophageal cancer is the eighth most prevalent cancer in the world and squamous cell carcinoma (ESCC) is the major histological type in East Asian countries.…”

CAG repeat size in Huntingtin alleles is associated with cancer prognosis

“…GEMO is the French branch of the international initiative CIMBA (Consortium of Investigators of Modifiers of BRCA1 and BRCA2), which aims at identifying modifiers of breast cancer risk through the collection of DNA and clinical data from a large number of BRCA1 and BRCA2 mutation carriers. [12][13][14] Participation in the GEMO cohort was proposed during the cancer clinic in which patients were informed of a positive BRCA1/2 test result. Their written informed consent was obtained.…”