Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A

Wang, Hansong; Burnett, Terrilea; Kono, Suminori; Haiman, Christopher A.; Iwasaki, Motoki; Wilkens, Lynne R.; Loo, Lenora W. M.; Berg, David Van Den; Kolonel, Laurence N.; Henderson, Brian E.; Keku, Temitope O.; Sandler, Robert S.; Signorello, Lisa B.; Blot, William J.; Newcomb, Polly A.; Pande, Mala; Amos, Christopher I.; West, Dee W.; Bézieau, Stéphane; Berndt, Sonja I.; Zanke, Brent W.; Hsu, Li; Lindor, Noralane M.; Haile, Robert W.; Hopper, John L.; Jenkins, Mark A.; Gallinger, Steven; Casey, Graham; Stenzel, Stephanie L.; Schumacher, Fredrick; Peters, Ulrike; Gruber, Stephen B.; Tsugane, Shoichiro; Stram, Daniel O.; Marchand, Loı̈c Le

doi:10.1038/ncomms5613

Cited by 70 publications

(69 citation statements)

References 26 publications

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“…The narrow-sense heritability estimates based on twin and family studies of CRC range from 12 to 35% 2,3 . Although several genome-wide association studies (GWAS) of CRC have successfully identified common single-nucleotide polymorphisms (SNPs) associated with CRC risk 4–21 , a large fraction of the heritability still remains elusive 22 . Our GWAS combines data from four large CRC consortia, the Colorectal Cancer Transdisciplinary (CORECT) Study, the Colon Cancer Family Registry (CFR), the Molecular Epidemiology of Colorectal Cancer (MECC) Study and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) to elucidate previously undiscovered susceptibility loci for CRC.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Schumacher¹,

Schmit²,

Jiao³

et al. 2015

Nat Commun

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147

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Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.

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Section: Introductionmentioning

confidence: 99%

Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Schumacher¹,

Schmit²,

Jiao³

et al. 2015

Nat Commun

Self Cite

147

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“…The residual disparity could be explained by factors that were not controlled in the analyses. SEER data do not collect information on other potentially important confounder such as the uses of over-the-counter medications and oral prescription drugs 56 , provider- and facility-related characteristics 57 , as well as genetics 58 , dietary 59 , environmental 60 , and biological factors 17 . A more complete assessment of major underlying factors is needed in order to inform the development of strategies that can further reduce or even completely eliminate the racial disparity in colon cancer survival.…”

Section: Discussionmentioning

confidence: 99%

Effects of Cancer Stage and Treatment Differences on Racial Disparities in Survival From Colon Cancer: A United States Population-Based Study

et al. 2016

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Background & Aims We evaluated differences in treatment of black vs white patients with colon cancer and assessed their effects on survival, based on cancer stage. Methods We collected data from the Surveillance, Epidemiology and End Results (SEER)-Medicare database and identified 6190 black and 61,951 white patients with colon cancer diagnosed from 1998 through 2009 and followed through 2011. Three sets of 6190 white patients were sequentially matched, using a minimum distance strategy, to the same set of 6190 black patients based on demographic (age, sex, diagnosis year, and SEER registry), tumor presentation (demographic plus comorbidities, tumor stage, grade, and size), and treatment (presentation plus therapies) variables. We conducted sensitivity analyses to explore the effects of socioeconomic status in a sub-cohort that included 2000 randomly selected black patients. Racial differences in treatment were assessed using a logistic regression model; their effects on racial survival disparity were evaluated using Kaplan-Meier method and Cox proportional hazards model. Results After patients were matched for demographic variables, the absolute 5 y difference in survival between black and white patients was 8.3% (white, 59.2% 5 y survival; blacks, 50.9% 5 y survival) (P<.0001); this value decreased significantly, to 5.0% (P<.0001), after patients were matched for tumor presentation, and decreased to 4.9% (P<.0001) when patients were matched for treatment. Differences in treatment therefore accounted for 0.1% of the 8.3% difference in survival between black and white patients. After patients were matched for tumor presentation, racial disparities were observed in almost all types of treatment; the disparities were most prominent for patients with advanced-stage cancer (stages III or IV, up to 11.1% difference) vs early-stage cancer (stages I or II, up to 4.3% difference). After patients were matched for treatment, there was a greater reduction in disparity for black vs white patients with advanced-stage compared with early-stage cancer. In sensitivity analyses, the 5 y racial survival disparity was 7.7% after demographic match, which was less than 8.3% observed in the complete cohort. This reduction was likely due to the differences between the sub-cohort and the complete cohort in those variables that were not included in the demographic match. This value was reduced to 6.5% (P=.0001) after socioeconomic status was included in the demographic match. The difference decreased significantly to 2.8% (P=.090) after tumor presentation match, but was not further reduced after treatment match. Conclusions We observed significant disparities in treatment and survival of black vs white patients with colon cancer. The disparity in survival appears to have been more strongly affected by tumor presentation at diagnosis than treatment. The effects of treatment differences on disparities in survival were greater for patients with advanced-stage, vs early-stage, cancer.

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“…Standard marker exclusion criteria were applied in each cancer consortium (5–11), and we have previously reported the summary of QC details in Hung et al (12). Genotype imputation was conducted for each cancer site using IMPUTE, BEAGLE, MACH and Minimac (imputation threshold of R 2 > 0.3) using the 1000 genome reference panel.…”

Section: Methodsmentioning

confidence: 99%

“…Logistic regression analysis using a log additive model was performed previously to test variant associations with cancer risk for the forty-five studies (5–11), providing per-allele odds ratios (ORs) adjusted for age, principal components and gender where applicable. Study-specific results were then combined for each cancer site using a fixed effects model.…”

Section: Methodsmentioning

confidence: 99%

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Kraft²,

et al. 2016

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Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression.

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Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A

Cited by 70 publications

References 26 publications

Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Effects of Cancer Stage and Treatment Differences on Racial Disparities in Survival From Colon Cancer: A United States Population-Based Study

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

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