ALDH3B2 Polymorphism Is Associated with Colorectal Cancer Susceptibility

Colorectal cancer (CRC) is the 5th leading cancer in China. Alcohol consumption has been reported to be one of the risk factors of CRC. However, it remains unclear whether genetic variants of alcohol metabolic genes are associated with CRC risk. In this study, we tested the coding variants in the alcohol metabolic genes and the risk of CRC, by using 485 cases and 516 controls. A total of 16 germline coding variants in 10 alcohol metabolic genes were genotyped. We identified that rs3741178 in ALDH3B2 was significantly associated with CRC risk with odds ratio being 2.13 (95% CI: 1.24–3.68, P=0.0064). Further functional annotation suggested that this variant may damage the protein function of ALDH3B2. Our results suggested that ALDH3B2 in the alcohol metabolism pathway contributed to the development of CRC, which may contribute to the prevention of this disease in the future.

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Evaluation of common genetic variants in vitamin E-related pathway genes and colorectal cancer susceptibility

Archives of Toxicology ◽

10.1007/s00204-021-03078-0 ◽

2021 ◽

Author(s):

Qiuyi Zhang ◽

Yixuan Meng ◽

Mulong Du ◽

Shuwei Li ◽

Junyi Xin ◽

...

Keyword(s):

Colorectal Cancer ◽

Vitamin E ◽

Genetic Variants ◽

Cancer Susceptibility ◽

Common Genetic Variants ◽

Related Pathway

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Association of Eleven Common, Low-Penetrance Colorectal Cancer Susceptibility Genetic Variants at Six Risk Loci with Clinical Outcome

PLoS ONE ◽

10.1371/journal.pone.0041954 ◽

2012 ◽

Vol 7 (7) ◽

pp. e41954 ◽

Cited By ~ 15

Author(s):

Janelle M. Hoskins ◽

Pei-Shi Ong ◽

Temitope O. Keku ◽

Joseph A. Galanko ◽

Christopher F. Martin ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Outcome ◽

Genetic Variants ◽

Cancer Susceptibility

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Genetic variants involved in the lipid metabolism pathway to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and MAVERICC trials.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.118 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 118-118

Author(s):

Jingyuan Wang ◽

Joshua Millstein ◽

Fotios Loupakis ◽

Sebastian Stintzing ◽

Hiroyuki Arai ◽

...

Keyword(s):

Colorectal Cancer ◽

Lipid Metabolism ◽

Genetic Variants ◽

Progression Free Survival ◽

Snp Markers ◽

Acid Oxidation ◽

Metabolism Pathway ◽

Increased Risk ◽

In Fire ◽

The Impact

118 Background: Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches the glucose-dependent metabolism to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer. Previous reports suggested that polymorphisms of the lipid metabolism-related genes are associated with the increased risk of CRC and poor clinical outcome in CRC. Therefore, we hypothesized that genetic variants in the lipid metabolism pathway may predict first-line treatment outcome in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, FIRE-3 and MAVERICC, was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 25 selected SNPs in 10 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1, LPCAT2, PPARG, CPT1A, ACSS2, SREBF1, FASN, ACACA) was analyzed. Those treated with FOLFIRI/ bevacizumab (bev) in FIRE-3 (n = 107) and MAVERICC (n = 163) served as discovery and validation cohorts respectively, while FIRE-3 FOLFIRI/ cetuximab (cet) (n = 129) arm was used as the control. Interaction between each SNP and treatment was evaluated in FIRE-3 (FOLFIRI/bev arm vs. FOLFIRI/cet arm). Results: In the discovery (FIRE-3 bev) cohort, pts with FASN rs4485435 any C allele (N = 21) showed significantly shorter progression-free survival (PFS) (8.69 vs 13.48 months) compared to carriers of G/G (N = 62) in both univariate (hazard ratio [HR] = 2.88; 95% confidence interval [CI]: 1.57-5.29; p = 0.00037) and multivariate (HR = 2.87; 95%CI 1.4-5.9; p = 0.00675) analyses. These data were validated in the MAVERICC bev cohort in multivariate analysis (11.17 vs 14.06 months; HR = 2.07; 95%CI: 1.15-3.74; p = 0.02). Pts carrying any T allele in PPARG rs3856806 (N = 36) showed significantly longer overall survival (OS) (Not reached vs 42 months) than carriers of C/C (n = 93) in the FIRE-3 cet cohort in both univariate (HR = 0.4; 95%CI 0.17-0.92; p = 0.03) and multivariate (HR = 0.37; 95%CI 0.15-0.93; p = 0.02) analyses, but the association was not observed in the bev cohort of MAVERICC and FIRE-3. In the comparison of bev arm vs cet arm in FIRE-3, interactions were shown with FASN rs4485435 (p = 0.017) on PFS and PPARG rs3856806 (p = 0.059) on OS. Conclusions: Our study demonstrates for the first time that FASN polymorphism could predict outcomes of bev-based treatment in mCRC patients; Meanwhile PPARG polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF/EGFR treatment.

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Exome sequencing and genotyping identify a rare variant in NLRP7 gene associated with ulcerative colitis

10.1101/182113 ◽

2017 ◽

Author(s):

Alexandros Onoufriadis ◽

Kristina Stone ◽

Antreas Katsiamides ◽

Ariella Amar ◽

Yasmin Omar ◽

...

Keyword(s):

Ulcerative Colitis ◽

Exome Sequencing ◽

Genetic Variants ◽

Odds Ratio ◽

High Throughput Sequencing ◽

Association Studies ◽

Common Disease ◽

Genome Wide Association Studies ◽

Increased Risk ◽

Coding Variants

AbstractBackground and aimsAlthough genome-wide association studies (GWAS) in inflammatory bowel disease (IBD) have identified a large number of common disease susceptibility alleles for both Crohn’s disease (CD) and ulcerative colitis (UC), a substantial fraction of IBD heritability remains unexplained, suggesting that rare coding genetic variants may also have a role in pathogenesis. We used high-throughput sequencing in families with multiple cases of IBD, followed by genotyping of cases and controls, to investigate whether rare protein altering genetic variants are associated with susceptibility to IBD.MethodsWhole exome sequencing was carried out in 10 families in which 3 or more individuals were affected with IBD. A stepwise filtering approach was applied to exome variants to identify potential causal variants. Follow-up genotyping was performed in 6,025 IBD cases (2,948 CD; 3,077 UC) and 7,238 controls.ResultsOur exome variant analysis revealed coding variants in the NLRP7 gene that were present in affected individuals in two distinct families. Genotyping of the two variants, p.S361L and p.R801H, in IBD cases and controls showed that the p.S361L variant was significantly associated with an increased risk of ulcerative colitis (odds ratio 4.79, p=0.0039) and IBD (odds ratio 3.17, p=0.037). A combined analysis of both variants showed suggestive association with an increased risk of IBD (odds ratio 2.77, p=0.018).ConclusionsThe results suggest that NLRP7 signalling and inflammasome formation may be a significant component in the pathogenesis of IBD.

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