Eluf-Neto, Jose*
      
        
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Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10(-10)) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust association between a truncating BRCA2 variant and UADT cancer risk suggests that treatment strategies orientated towards BRCA2 mutations may warrant further investigation in UADT tumors.
- MeSH
 - dospělí MeSH
 - genetická predispozice k nemoci MeSH
 - hodnocení rizik MeSH
 - jednonukleotidový polymorfismus * MeSH
 - kouření škodlivé účinky epidemiologie MeSH
 - lidé středního věku MeSH
 - lidé MeSH
 - logistické modely MeSH
 - nádory hlavy a krku genetika MeSH
 - odds ratio MeSH
 - pití alkoholu škodlivé účinky epidemiologie MeSH
 - protein BRCA2 genetika MeSH
 - rizikové faktory MeSH
 - senioři MeSH
 - spinocelulární karcinom genetika MeSH
 - studie případů a kontrol MeSH
 - Check Tag
 - dospělí MeSH
 - lidé středního věku MeSH
 - lidé MeSH
 - mužské pohlaví MeSH
 - senioři MeSH
 - ženské pohlaví MeSH
 - Publikační typ
 - časopisecké články MeSH
 - Research Support, N.I.H., Extramural MeSH
 
Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.
- MeSH
 - demografie MeSH
 - DNA opravný a rekombinační protein Rad52 genetika MeSH
 - fyzikální mapování chromozomů MeSH
 - genetická predispozice k nemoci * MeSH
 - genetické lokusy * MeSH
 - jednonukleotidový polymorfismus genetika MeSH
 - lidé středního věku MeSH
 - lidé MeSH
 - lidské chromozomy, pár 12 genetika MeSH
 - lokus kvantitativního znaku genetika MeSH
 - nádory hlavy a krku genetika MeSH
 - nádory plic genetika MeSH
 - počítačová simulace MeSH
 - rizikové faktory MeSH
 - spinocelulární karcinom genetika MeSH
 - studie případů a kontrol MeSH
 - zárodečné buňky MeSH
 - Check Tag
 - lidé středního věku MeSH
 - lidé MeSH
 - mužské pohlaví MeSH
 - ženské pohlaví MeSH
 - Publikační typ
 - časopisecké články MeSH
 - Research Support, N.I.H., Extramural MeSH
 
We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10(-8)), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10(-9)). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10(-6)) than in HPV-negative (OR = 0.75, P = 0.16) cancers.
- MeSH
 - celogenomová asociační studie * MeSH
 - genetická predispozice k nemoci * MeSH
 - genetická variace genetika MeSH
 - genetické markery genetika MeSH
 - haplotypy genetika MeSH
 - HLA antigeny MeSH
 - infekce papilomavirem genetika virologie MeSH
 - lidé středního věku MeSH
 - lidé MeSH
 - nádory hltanu genetika virologie MeSH
 - nádory úst genetika virologie MeSH
 - Papillomaviridae izolace a purifikace MeSH
 - senioři MeSH
 - studie případů a kontrol MeSH
 - ústa metabolismus patologie virologie MeSH
 - Check Tag
 - lidé středního věku MeSH
 - lidé MeSH
 - mužské pohlaví MeSH
 - senioři MeSH
 - ženské pohlaví MeSH
 - Publikační typ
 - časopisecké články MeSH
 - srovnávací studie MeSH
 
BACKGROUND: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. METHODS: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. RESULTS: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. CONCLUSIONS: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.
- MeSH
 - adenokarcinom plic epidemiologie MeSH
 - dlaždicobuněčné karcinomy hlavy a krku epidemiologie MeSH
 - homeostáza telomer genetika MeSH
 - leukocyty metabolismus MeSH
 - lidé středního věku MeSH
 - lidé MeSH
 - lidské chromozomy, pár 5 genetika MeSH
 - mendelovská randomizace MeSH
 - nádory hlavy a krku epidemiologie MeSH
 - nádory plic epidemiologie MeSH
 - senioři nad 80 let MeSH
 - senioři MeSH
 - spinocelulární karcinom epidemiologie MeSH
 - telomery metabolismus MeSH
 - Check Tag
 - lidé středního věku MeSH
 - lidé MeSH
 - mužské pohlaví MeSH
 - senioři nad 80 let MeSH
 - senioři MeSH
 - ženské pohlaví MeSH
 - Publikační typ
 - časopisecké články MeSH
 - práce podpořená grantem MeSH
 - Research Support, N.I.H., Extramural MeSH
 - Research Support, U.S. Gov't, Non-P.H.S. MeSH