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

Rachakonda, P. Sivaramakrishna; Kong, Hai-ying; Srinivas, Nalini; García-Casado, Zaida; Requena, Celia; Fallah, Mahdi; Heidenreich, Barbara; Planelles, Dolores; Traves, Víctor; Schadendorf, Dirk; Nagore, Eduardo; Kumar, Rajiv

doi:10.1002/gcc.22669

Cited by 42 publications

(63 citation statements)

References 52 publications

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“…However, our data show that increased TERT expression in BCC tumors can be primarily attributed to the promoter mutations as shown in adult gliomas 37 . Telomeres in tumors with the TERT promoter mutations are usually shorter than in tumors without those mutations as observed in melanoma and gliomas 35,38 . However, we did not observe a statistically significant difference in telomere length in BCC tumors.…”

Section: Discussionmentioning

confidence: 98%

Coding and noncoding somatic mutations in basal cell carcinoma

Maturo

Rachakonda

Heidenreich

et al. 2019

Preprint

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Basal cell carcinoma (BCC) represents the most commonly diagnosed human cancer among persons of European ancestry with etiology mainly attributed to sun-exposure. In this study we investigated mutations in coding and flanking regions of the PTCH1 and TP53 genes and noncoding alterations in the TERT and DPH3 promoters in 191 BCC tumors. In addition, we measured CpG methylation within the TERT hypermethylated oncological region (THOR) and transcriptions levels of the reverse transcriptase subunit. We observed mutations in PTCH1 in 59% and TP53 in 31% of the tumors. Noncoding mutations in TERT and DPH3 promoters were detected in 59% and 38% of the tumors, respectively. We observed a statistically significant co-occurrence of mutations at the four investigated loci. While PTCH1 mutations tended to associate with decreased patient age at diagnosis; TP53 mutations were associated with light skin color and increased number of nevi; TERT and DPH3 promoter with history of cutaneous neoplasms in BCC patients. TERT promoter mutations but not THOR methylation associated with an increased expression of the reverse transcriptase subunit.Our study signifies, in addition to the protein altering mutations in the PTCH1 and TP53 genes, the importance of noncoding mutations in BCC, particularly functional alterations in the TERT promoter. Introduction,

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Section: Discussionmentioning

confidence: 98%

Coding and noncoding somatic mutations in basal cell carcinoma

Maturo

Rachakonda

Heidenreich

et al. 2019

Preprint

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“…The associations between the instrument-outcome were estimated using logistic regression at the allele levels in the study population. A one-sample MR study was conducted using non-overlapping datasets in the same population (33). Two datasets were generated for cases and controls based on similar mean and variance for arsenic exposure.…”

Section: Discussionmentioning

confidence: 99%

“…The observational studies have consistently shown statistically significant associations between long telomeres and increased cancer risk (27,35,36). The genetic basis for those observations are provided by the studies showing that various polymorphisms that modulate telomere length also affect the risk of different cancers, with alleles segregating with increased telomere length associating with increased risk (10,11,37).…”

Section: Discussionmentioning

confidence: 99%

“…Relative leukocyte telomere length was measured in DNA from 528 BCC cases and 533 healthy controls using a multiplex quantitative real time PCR based assay, as described earlier by Cawthon et al, with minor modifications (26,27). Briefly, each reaction was performed in triplicates in optical 384-well reaction plates, in a 10µl volume, using 2µl of 5X HOT FIREPol probe qPCR Mix Plus with ROX (Solis BioDyne, Tartu, Estonia), 1.5µM of Syto-9 (Invitrogen, Thermo Fischer Scientific Inc., USA) and 5-10ng of genomic DNA.…”

Section: Measurement Of Relative Leukocyte Telomere Lengthmentioning

confidence: 99%

“…In addition, the P value for heterogeneity test statistic was statistically significant implying failure of instrumental variable assumptions for at least one of the SNPs (P = 0.01 with 8 degrees of freedom) ( Supplementary Figure S1 and Supplementary Table S5). Since arsenic exposure was found to be a statistically significant confounder, we carried out Mendelian randomization using a one-sample study with non-overlapping datasets to determine the effect of telomere length on BCC risk (33).…”

Section: Mendelian Randomizationmentioning

confidence: 99%

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Telomere length, arsenic exposure and risk of basal cell carcinoma of skin

Srinivas

Rachakonda

Hielscher

et al. 2018

Preprint

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Telomere length per se a heritable trait has been reported to be associated with different diseases including cancers. In this study based on arsenic exposed 528 cases with basal cell carcinoma of skin (BCC) and 533 healthy controls, we observed a statistically significant association between decreased telomere length and increased BCC risk (OR = 5.92, 95% CI = 3.92-9.01, P<0.0001). We also observed that higher arsenic exposure (>1.32 µg/L) was statistically significantly associated with decreased telomere length (β = -0.026, 95% CI = -0.05--0.003, P = 0.02). The interaction between arsenic exposure and telomere length on BCC risk was statistically significant (P = 0.02). Within each tertile based on arsenic exposure, the individuals with shorter telomeres were at an increased risk of BCC, with highest risk being in the highest exposed group (OR = 16.13, 95% CI = 6.71-40.00, P<0.0001); followed by those in medium exposure group (OR = 5.05, 95% CI = 2.29-10.20, P <0.0001), and low exposure group (OR = 3.44, 95% CI = 1.81-6.54, P = 0.0002). The combined effect of highest arsenic exposure and shortest telomeres on the risk of BCC (OR = 10.56, 95% CI = 5.14-21.70) showed a statistically significant departure from additivity (interaction constant ratio 6.56, P = 0.03). Our results show that in the presence of arsenic exposure, decreased telomere length predisposes individuals to increased risk of BCC, with the effect being synergistic in individuals with highest arsenic exposure and shortest telomeres.

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Association between telomere length and hepatocellular carcinoma risk: A Mendelian randomization study

Yang

Chen

et al. 2023

Cancer Medicine

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Background Hepatocellular carcinoma (HCC) is a common cancer threatening the public health globally. Although HCC has been associated with the telomere length (TL), the causal relationship between them is not well understood. Therefore, we attempted to explore the linear causal relationship between TL and HCC through Mendelian randomization (MR) analysis among Asian and European populations. Methods The summary statistics of TL‐associated single nucleotide polymorphisms (SNPs) were obtained from a genome‐wide association study (GWAS) in the Asian population ( N = 23,096). The data of TL‐associated SNPs in the European population ( N = 472,174) and the GWAS summary statistics of HCC in the Asian population (1866 cases, 195,745 controls) as well as the European population (168 cases, 372,016 controls) were downloaded from the public GWAS database. Two‐sample MR was performed using inverse variance weighting (IVW), weighted median estimate, MR–Egger regression, weighted‐mode estimate, and simple‐mode estimate methods. Sensitivity analysis was performed to text the primary results' robustness. Results Nine SNPs associated with TL in Asian populations and 98 SNPs in European populations were selected as instrumental variables. No linear causal relationship between heritable TL and the HCC risk was recorded in the Asian (IVW analysis odds ratio [OR] = 1.023, 95% confidence interval [CI] 0.745, 1.405, p = 0.887) and European populations (IVW analysis OR = 0.487, 95% CI 0.180, 1.320, p = 0.157). Other methods also achieved similar outcomes. Sensitivity analysis was performed and revealed no heterogeneity and horizontal pleiotropy. Conclusions No linear causal association was recorded between heritable TL and HCC in Asian and European populations.

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

Cited by 42 publications

References 52 publications

Coding and noncoding somatic mutations in basal cell carcinoma

Coding and noncoding somatic mutations in basal cell carcinoma

Telomere length, arsenic exposure and risk of basal cell carcinoma of skin

Association between telomere length and hepatocellular carcinoma risk: A Mendelian randomization study

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