<i>DCAF4</i>, a novel gene associated with leucocyte telomere length

Mangino, Massimo; Christiansen, Lene; Stone, Rivka C.; Hunt, Steven C.; Horvath, Kent; Eisenberg, Dan T. A.; Kimura, Masayuki; Petersen, Inge; Kark, Jeremy D.; Herbig, Utz; Reiner, Alex P.; Bénétos, Athanase; Codd, Veryan; Nyholt, Dale R.; Sinnreich, Ronit; Christensen, Kaare; Nassar, Hisham; Hwang, Shih Jen; Levy, Daniel; Bataille, Véronique; Fitzpatrick, Annette L.; Chen, Wei; Berenson, Gerald S.; Samani, Nilesh J.; Martin, Nicholas G.; Tishkoff, Sarah A.; Schork, Nicholas J.; Kyvik, Kirsten Ohm; Dalgård, Christine; Spector, Timothy D.; Aviv, Abraham

doi:10.1136/jmedgenet-2014-102681

Cited by 68 publications

(66 citation statements)

References 54 publications

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“…16 Presumably, the mutation imparts unlimited capacity for proliferation of the melanocytic nevi as suggested by the association of longer telomeres with increased number of nevi. 37,38 Moreover, multiple alleles shown to be associated in genome-wide association studies with increased telomere length are also known to increase risk for various cancers. 17 In analogy, we hypothesize that the longer constitutive telomere length in melanoma patients or patients with other cancers as seen in this and previous studies may represent genetically determined stochastically increased basal telomerase levels that impart a proliferative advantage, as also indicated by a faster age-dependent telomere attrition in patients than in controls.…”

Section: Discussionmentioning

confidence: 99%

Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk

Rachakonda

Kong

Srinivas

et al. 2018

Genes Chromosomes & Cancer

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Telomere repeats at chromosomal ends, critical for genomic integrity, undergo age-dependent attrition and telomere length has been associated with different disorders including cancers. In this study, based on 1469 patients and 1158 healthy controls, we show a statistically significant (P = 6 × 10 ) association between increased telomere length and melanoma risk. Mendelian randomization, using 5 telomere length-associated polymorphisms, ruled out confounding factors or reverse causality and showed association between increased telomere length and melanoma risk with odds ratio of 2.66 (95% confidence interval: 2.07-3.25). Age-dependent telomere attrition was faster in melanoma cases than controls (P = .01). The carriers of a highly penetrant germline -57A>C TERT promoter mutation, in a previously reported melanoma family, had longer telomeres than the noncarriers. The mutation causes increased TERT and telomerase levels through creation of a binding motif for E-twenty six (ETS) transcription factors and the carriers develop melanoma with an early age of onset and rapid progression to metastasis. In analogy, we hypothesize that increased telomere length in melanoma patients reflects stochastic increased telomerase levels due to common genetic variation. Paradoxically, we observed shorter telomeres (P = 1 × 10 ) in primary tumors from unrelated melanoma patients with (121) than without (170) somatic TERT promoter mutations that similar to the germline mutation, also create binding motifs for ETS transcription factors. However, the age-dependent telomere attrition was faster in tumors with the TERT promoter mutations than in those without such mutations. Besides a robust association between increased telomere length and risk, our data show a perturbed telomere homeostasis in melanoma.

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Section: Discussionmentioning

confidence: 99%

Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk

Rachakonda

Kong

Srinivas

et al. 2018

Genes Chromosomes & Cancer

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“…Support for this notion is provided, for instance, by findings that polygenetic adaptation might partially explain the shorter TL in individuals of European ancestry compared to those of African ancestry [33]. Such an adaptation might have attenuated the increased risk of depigmented skin to sporadic melanoma [34]. …”

Section: Evolutionary and Epidemiological Perspectivesmentioning

confidence: 99%

Mutations, Cancer and the Telomere Length Paradox

2017

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Individuals with short telomeres should be at increased risk for cancer, since short telomeres lead to genomic instability— a hallmark of cancer. However, individuals with long telomeres also display an increased risk for major cancers, thus creating a cancer-telomere length paradox. The two-stage clonal expansion model we propose is based on the thesis that a series of mutational hits (1st Hit) at the stem-cell level generates a clone with replicative advantage. A series of additional mutational hits (2nd Hit) transforms the expanding clone into cancer. By proposing that the 1st Hit is largely telomere length-independent, while the 2nd Hit is largely telomere length-dependent, we resolve the paradox, highlighting a regulatory role of telomeres in cancer.

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“…Germline SNPs in TERC, TERT, RTEL1, NAF1, and OBFC1 have been associated with telomere length in genome‐wide association studies (GWAS). Additional genes associated with telomere length include: BICD1, ACYP2 , ZNF208 , MPHOSPH6, and DCAF4 …”

Section: Introductionmentioning

confidence: 99%

Telomere structure and maintenance gene variants and risk of five cancer types

Karami

Han

Pande

et al. 2016

Intl Journal of Cancer

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Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level P-value cutoffs ≤3.08×10−5). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the TERT-CLPTML1 region, rs12655062 was associated positively with prostate cancer, and inversely with colorectal and ovarian cancers, and rs115960372 was associated positively with prostate cancer. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and ovarian cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.

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DCAF4, a novel gene associated with leucocyte telomere length

Cited by 68 publications

References 54 publications

Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk

Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk

Mutations, Cancer and the Telomere Length Paradox

Telomere structure and maintenance gene variants and risk of five cancer types

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