Genetic dissection of intermediate phenotypes as a way to discover novel cancer susceptibility alleles

Carvajal‐Carmona, Luis G.

doi:10.1016/j.gde.2010.03.013

Cited by 5 publications

(4 citation statements)

References 66 publications

(71 reference statements)

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“…A gradual decrease of DRC with increasing TNM stage in a surrogate tissue possibly reflects important biological phenomenon in relation to progression of the disease. Deficient or reduced NER-DRC was already reported as a risk factor for several different cancers, including bladder (18), breast (21,22), skin (23)(24)(25), head and neck (14,32,33), lung (34)(35)(36)(37) and prostate cancer (38), as summarized in Table I. Our results contribute to the list of evidences on the importance of NER-DRC in carcinogenesis, showing the same relevance also for sporadic CRC.…”

Section: Discussionsupporting

confidence: 79%

Differences in nucleotide excision repair capacity between newly diagnosed colorectal cancer patients and healthy controls

Slyšková¹,

Naccarati²,

Pardini³

et al. 2012

Mutagenesis

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Alteration of DNA integrity is a potential cause of cancer and it is assumed that reduced DNA repair capacity and accumulation of DNA damage may represent intermediate markers in carcinogenesis. In this case-control study, DNA damage and nucleotide excision repair capacity (NER-DRC) were assessed in association with sporadic colorectal cancer (CRC). Both parameters were quantified by comet assay in blood cells of 70 untreated incident patients and 70 age-matched healthy controls. mRNA expression and polymorphisms in relevant NER genes were concurrently analyzed. The aim of this study was to characterize incident CRC patients for NER-DRC and to clarify possible relations between investigated variables. Comet assay and mRNA expression analysis showed that CRC patients differ in repair capacity as compared to controls. Patients had a lower NER-DRC and simultaneously they exhibited higher endogenous DNA damage (for both P < 0.001). Accumulation of DNA damage and decreasing NER-DRC behaved as independent modulating parameters strongly associated with CRC. Expression levels of 6 out of 9 studied genes differed between groups (P ≤ 0.001), but none of them was related to DRC or to any of the studied NER polymorphisms. However, in patients only, XPC Ala499Val modulated expression levels of XPC, XPB and XPD gene, whereas XPC Lys939Gln was associated with XPA expression level in controls (for all P < 0.05). This study provides evidence on altered DRC and DNA damage levels in sporadic CRC and proposes the relevance of the NER pathway in this malignancy. Further, alterations in a complex multigene process like DNA repair may be better characterized by functional quantification of repair capacity than by quantification of individual genes transcripts or gene variants alone.

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Section: Discussionsupporting

confidence: 79%

Differences in nucleotide excision repair capacity between newly diagnosed colorectal cancer patients and healthy controls

Slyšková¹,

Naccarati²,

Pardini³

et al. 2012

Mutagenesis

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“…These data, although obtained in a limited number of cases, suggests that rs6983267G might increase the risk of tumor progression rather than initiation or that rs6983267G could be associated with the risk of more aggressive tumors. Although further studies should assess this finding in more detail and in a significantly higher patient sample size, our data in these small set of 235 patients are consistent with our previous study in colorectal adenomas, a risk factor and an intermediate phenotype for colorectal cancer (Carvajal-Carmona 2010) where we showed that known colorectal cancer SNPs acted at different stages of tumorigenesis, some affecting cancer initiation and some others affecting cancer progression (Carvajal-Carmona, et al 2013). …”

Section: Resultssupporting

confidence: 90%

The 8q24 rs6983267G variant is associated with increased thyroid cancer risk

Sahasrabudhe

Estrada

Lott

et al. 2015

Endocrine-Related Cancer

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The G allele of the rs6983267 single nucleotide polymorphism, located on chromosome 8q24, has been associated with increased risk of several cancer types. The association between rs6983267G and thyroid cancer has been tested in different populations, mostly of European ancestry, and has led to inconclusive results. While significant associations have been reported in the British and Polish populations, no association has been detected in populations from Spain, Italy and the USA. To further investigate the role of rs6983267G in thyroid cancer susceptibility, we evaluated rs6983267 genotypes in three populations of different continental ancestry (British Isles, Colombia and Japan), providing a total of 3,067 cases and 8,575 controls. We detected significant associations between rs6983267G and thyroid cancer in the British Isles (Odds Ratio, OR= 1.19, 95% confidence interval, CI: 1.11–1.27, P= 4.03 × 10−7), Japan (OR= 1.20, 95% CI: 1.03–1.41, P= 0.022) and a borderline significant association of similar effect direction and size in Colombia (OR= 1.19, 95% CI: 0.99–1.44, P= 0.069). A meta-analysis of our multi-ethnic study and previously published non-overlapping datasets, which included a total of 5,484 cases and 12,594 controls, confirmed the association between rs6983267G and thyroid cancer (P= 1.23 × 10−7, OR= 1.13, 95% CI: 1.07–1.18). Our results therefore support the notion that rs6983267G is a bona fide thyroid cancer risk variant that increases the risk of disease by ~13%.

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“…We capitalized initially upon a homogeneous patient population with detailed clinical data with 80% power to detect a HR as small as 1.46, assuming MAF=0.20, α= 0.05, and dominance. Prior to committing additional expenditure, we conducted in silico analysis of the top hits using publicly-available data including exploration of a possible intermediate phenotype (41). In addition to the statistical significance of the combined association, the biology of the most-significant gene was compelling (as is always the case in candidate gene studies).…”

Section: Discussionmentioning

confidence: 99%

Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

Goode

Chenevix-Trench

Hartmann

et al. 2011

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Invasive ovarian cancer is a significant cause of gynecologic cancer mortality. Methods We examined whether this mortality was associated with inherited variation in ~170 candidate genes/regions (993 SNPs) in a multi-stage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue micro-arrays (TMAs, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths). Results The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR 1.7, 95% CI 1.3–2.2, p=2.0×10−5) and with overall variation in HGF (gene-level test, p=3.7×10−4). Analysis of TCGA data revealed consistent associations (e.g., rs5745709 [r2=0.96 with rs1800793]: TCGA 2.4, 1.4–4.1, p=2.2×10−3; Mayo Clinic+TCGA 1.6, 1.3–1.9, p=7.0×10−5) and suggested genotype correlation with reduced HGF mRNA levels (p=0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET, and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (p=0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (1.0, 0.9–1.1, p=0.87). Conclusions We conclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that genetic variation plays a major role in ovarian cancer mortality; any minor role is not related to genetically-determined expression. Impact Our study demonstrates the utility of multiple data types and multiple datasets in observational studies.

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Genetic dissection of intermediate phenotypes as a way to discover novel cancer susceptibility alleles

Cited by 5 publications

References 66 publications

Differences in nucleotide excision repair capacity between newly diagnosed colorectal cancer patients and healthy controls

Differences in nucleotide excision repair capacity between newly diagnosed colorectal cancer patients and healthy controls

The 8q24 rs6983267G variant is associated with increased thyroid cancer risk

Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

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