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Fulltext Human Papillomavirus 16 E6 Antibodies in Individuals without Diagnosed Cancer: A Pooled Analysis

Lang Kuhs KA, Anantharaman D, Waterboer T, Johansson M, Brennan P, Michel A, et al.

Cancer Epidemiol Biomarkers Prev, 2015 Apr;24(4):683-9.
PMID: 25623733 DOI: 10.1158/1055-9965.EPI-14-1217

BACKGROUND: The increasing incidence of oropharyngeal cancer in many developed countries has been attributed to human papillomavirus type 16 (HPV16) infections. Recently, HPV16 E6 serology has been identified as a promising early marker for oropharyngeal cancer. Therefore, characterization of HPV16 E6 seropositivity among individuals without cancer is warranted.
METHODS: A total of 4,666 controls were pooled from several studies of cancer and HPV seropositivity, all tested within the same laboratory. HPV16 E6 seropositive controls were classified as having (i) moderate [mean fluorescent intensity (MFI) ≥ 484 and <1,000] or (ii) high seroreactivity (MFI ≥ 1,000). Associations of moderate and high HPV16 E6 seroreactivity with (i) demographic risk factors; and seropositivity for (ii) other HPV16 proteins (E1, E2, E4, E7, and L1), and (iii) E6 proteins from non-HPV16 types (HPV6, 11, 18, 31, 33, 45, and 52) were evaluated.
RESULTS: Thirty-two (0.7%) HPV16 E6 seropositive controls were identified; 17 (0.4%) with moderate and 15 (0.3%) with high seroreactivity. High HPV16 E6 seroreactivity was associated with former smoking [odds ratio (OR), 5.5; 95% confidence interval (CI), 1.2-51.8], and seropositivity against HPV16 L1 (OR, 4.8; 95% CI, 1.3-15.4); E2 (OR, 7.7; 95% CI, 1.4-29.1); multiple HPV16 proteins (OR, 25.3; 95% CI, 2.6-119.6 for three HPV16 proteins beside E6) and HPV33 E6 (OR, 17.7; 95% CI, 1.9-81.8). No associations were observed with moderate HPV16 E6 seroreactivity.
CONCLUSIONS: High HPV16 E6 seroreactivity is rare among individuals without diagnosed cancer and was not explained by demographic factors.
IMPACT: Some HPV16 E6 seropositive individuals without diagnosed HPV-driven cancer, especially those with seropositivity against other HPV16 proteins, may harbor a biologically relevant HPV16 infection.
Fulltext Corrigendum re "Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma" [Eur Urol 2017;72:747-54]

Machiela MJ, Hofmann JN, Carreras-Torres R, Brown KM, Johansson M, Wang Z, et al.

Eur Urol, 2018 Sep;74(3):e85-e86.
PMID: 29853305 DOI: 10.1016/j.eururo.2018.05.017
Fulltext Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

Machiela MJ, Hofmann JN, Carreras-Torres R, Brown KM, Johansson M, Wang Z, et al.

Eur Urol, 2017 Nov;72(5):747-754.
PMID: 28797570 DOI: 10.1016/j.eururo.2017.07.015

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.
OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.
DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.
RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).
CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.
PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
Fulltext Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry

Figueroa JD, Middlebrooks CD, Banday AR, Ye Y, Garcia-Closas M, Chatterjee N, et al.

Hum Mol Genet, 2016 Mar 15;25(6):1203-14.
PMID: 26732427 DOI: 10.1093/hmg/ddv492

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
Fulltext Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

Machiela MJ, Zhou W, Karlins E, Sampson JN, Freedman ND, Yang Q, et al.

Nat Commun, 2016 06 13;7:11843.
PMID: 27291797 DOI: 10.1038/ncomms11843

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.