Common 5p15.33 and 6p21.33 variants influence lung cancer risk

Abstract

We conducted a genome-wide association (GWA) study of lung cancer comparing 511,919 SNP genotypes in 1,952 cases and 1,438 controls. The most significant association was attained at 15q25.1 (rs8042374; P = 7.75 × 10 −12 ), confirming recent observations. Pooling data with two other GWA studies (5,095 cases, 5,200 controls) and with replication in an additional 2,484 cases and 3,036 controls, we identified two newly associated risk loci mapping to 6p21.33 (rs3117582, BAT3-MSH5; P combined = 4.97 × 10 −10 ) and 5p15.33 (rs401681, CLPTM1L; P combined = 7.90 × 10 −9 ). Support for inherited genetic susceptibility to lung cancer has recently come from genomewide association studies that have demonstrated that 15q25.1 variation influences lung cancer risk 1-3 .To identify risk variants for lung cancer, we carried out a GWA study. Using Illumina HumanHap550 BeadChips, we genotyped 561,466 SNPs in 1,978 cases (Supplementary Methods online). After application of quality control criteria, genotypes were available for 1,952 cases. We were able to satisfactorily genotype 552,947 SNPs (98.5%) with mean sample call rate 99.7%. For controls, we used publicly accessible HumanHap550 genotype data in 1,438 individuals from the 1958 Birth Cohort 4 (Supplementary Methods). Genotypes were available for 541,327 SNPs (97.5% of 555,352 SNPs typed) and 524,714 SNPs were common to cases and controls. Applying quality control filters, we excluded 8,534 SNPs monomorphic in either cases or controls; 2,744 with call rates < 95%; 770 showing departure from HardyWeinberg equilibrium (HWE; P < 10 −5 in cases or controls) and 747 with minor allele frequency (MAF) <1% in cases or controls; leaving 511,919 informative SNPs for analysis.

Genetic Variations in TERT-CLPTM1L Genes and Risk of Lung Cancer in a Chinese Population

“…Recently, genetic variants in telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane1-like (CLPTM1L) locus at chromosome 5p15.33 have been identified to be related to lung cancer by several genome-wide association studies (GWAS) (McKay et al, 2008;Wang et al, 2008;Rafnar et al,cellular immortality and carcinogenesis of various cancers (Hanahan et al, 2000). Normally, TERT is only expressed in embryonic stem cells and germ cells; however, abnormal expression of TERT mRNA and protein has been observed in multiple types of tumors, including lung cancer (Hiyama et al, 1995;Falchetti et al, 2000;Wang et al, 2002).…”

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.…”

The pursuit of genome-wide association studies: where are we now?

“…[85][86][87] For lung cancer, the first convincing genetic locus also emerged, 15q25, which contained several genes encoding for nicotinic acetylcholine receptors. [88][89][90] The combination of three GWAS further identified additional susceptibility loci for this common cancer, 75 where one of the loci (5p15.33) was also identified by another GWAS. 91 The 5p15.33 locus contains two genes, TERT and CLPTM1L, and interestingly the sequence variants at this locus were found to be associated with several cancers.…”

“…As expected, the effect sizes for all the SNPs that were identified from this metaanalysis study were small (OR o1.2). After this first study, several GWAS meta-analysis have also been performed for various diseases such as CD, 69 T1D, 70,71 multiple sclerosis, 72 rheumatoid arthritis, 73 colorectal cancer 74 and lung cancer, 75 among other diseases.…”