A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer

Abstract

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10−10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10−9), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10−9). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.

Co-occurrence of Myeloproliferative Neoplasms and Solid Tumors Is Attributed to a Synergism Between Cytoreductive Therapy and the Common TERT Polymorphism rs2736100

“…Associations with cancers affecting skin (20), lung (21)(22)(23), colon (24), prostate (25), breast (26), testicle (27), bladder (28), and brain (29) were reported. Predisposition to hematologic malignancies such as acute lymphoid leukemia (18), and chronic lymphoid leukemia (30,31), and recently MPN (4-6) were also linked to the TERT locus.…”

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.…”

Novel and known genetic variants for male breast cancer risk at 8q24.21, 9p21.3, 11q13.3 and 14q24.1: Results from a multicenter study in Italy

“…In addition, we aimed to evaluate whether other common low-penetrance susceptibility alleles, recently identified and associated with BC risk in women [15,25,26], may also influence BC risk in men. Finally, we explored possible associations between SNPs and clinical-pathologic characteristics of MBC, in order to provide further insight into the biological basis of BC in men, and eventually improve both the identification of men at risk to develop this rare disease and the personalised clinical management of MBC patients.…”