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1

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Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Schmit, Stephanie L ; Edlund, Christopher K ; Schumacher, Fredrick R ; [et al.]

Oxford University Press (OUP) ; 2019

In: JNCI: Journal of the National Cancer Institute Vol. 111, No. 2 ( 2019-02-01), p. 146-157

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In: JNCI: Journal of the National Cancer Institute, Oxford University Press (OUP), Vol. 111, No. 2 ( 2019-02-01), p. 146-157

Abstract: Previous genome-wide association studies (GWAS) have identified 42 loci (P 〈 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P 〈 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P 〈 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Type of Medium: Online Resource

ISSN: 0027-8874 , 1460-2105

URL: Article

DOI: 10.1093/jnci/djy099

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XA 10000

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2019

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detail.hit.zdb_id: 1465951-7

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Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study

Tsilidis, Konstantinos K ; Papadimitriou, Nikos ; Dimou, Niki ; [et al.]

Elsevier BV ; 2021

In: The American Journal of Clinical Nutrition Vol. 113, No. 6 ( 2021-06), p. 1490-1502

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In: The American Journal of Clinical Nutrition, Elsevier BV, Vol. 113, No. 6 ( 2021-06), p. 1490-1502

Type of Medium: Online Resource

ISSN: 0002-9165

URL: Article

DOI: 10.1093/ajcn/nqab003

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XA 18600

Language: English

Publisher: Elsevier BV

Publication Date: 2021

detail.hit.zdb_id: 1496439-9

SSG: 12

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Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk

Thomas, Minta ; Sakoda, Lori C. ; Hoffmeister, Michael ; [et al.]

Elsevier BV ; 2020

In: The American Journal of Human Genetics Vol. 107, No. 3 ( 2020-09), p. 432-444

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In: The American Journal of Human Genetics, Elsevier BV, Vol. 107, No. 3 ( 2020-09), p. 432-444

Type of Medium: Online Resource

ISSN: 0002-9297

URL: Article

DOI: 10.1016/j.ajhg.2020.07.006

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Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 1473813-2

SSG: 12

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4

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Response to Li and Hopper

Thomas, Minta ; Sakoda, Lori C. ; Hoffmeister, Michael ; [et al.]

Elsevier BV ; 2021

In: The American Journal of Human Genetics Vol. 108, No. 3 ( 2021-03), p. 527-529

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In: The American Journal of Human Genetics, Elsevier BV, Vol. 108, No. 3 ( 2021-03), p. 527-529

Type of Medium: Online Resource

ISSN: 0002-9297

URL: Article

DOI: 10.1016/j.ajhg.2021.02.003

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XA 10000

Language: English

Publisher: Elsevier BV

Publication Date: 2021

detail.hit.zdb_id: 1473813-2

SSG: 12

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5

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Functional informed genome‐wide interaction analysis of body mass index, diabetes and colorectal cancer risk

Xia, Zhiyu ; Su, Yu‐Ru ; Petersen, Paneen ; [et al.]

Wiley ; 2020

In: Cancer Medicine Vol. 9, No. 10 ( 2020-05), p. 3563-3573

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In: Cancer Medicine, Wiley, Vol. 9, No. 10 ( 2020-05), p. 3563-3573

Abstract: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. Methods To improve statistical power and interpretation for gene‐environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m 2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype‐Tissue Expression Project for all genes with heritability ≥1%. We used a mixed‐effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI‐CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR 〈 0.2. Results Among 4839 genes tested, genetically predicted expressions of FOXA1 ( P = 3.15 × 10 −5 ), PSMC5 ( P = 4.51 × 10 −4 ) and CD33 ( P = 2.71 × 10 −4 ) modified the association of BMI on CRC risk for men; KIAA0753 ( P = 2.29 × 10 −5 ) and SCN1B ( P = 2.76 × 10 −4 ) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes ( P = 2.31 × 10 −5 ). Conclusions Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

Type of Medium: Online Resource

ISSN: 2045-7634 , 2045-7634

URL: Issue

URL: Article

DOI: 10.1002/cam4.v9.10

DOI: 10.1002/cam4.2971

Language: English

Publisher: Wiley

Publication Date: 2020

detail.hit.zdb_id: 2659751-2

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Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region

Jordahl, Kristina M. ; Shcherbina, Anna ; Kim, Andre E. ; [et al.]

American Association for Cancer Research (AACR) ; 2022

In: Cancer Epidemiology, Biomarkers & Prevention Vol. 31, No. 5 ( 2022-05-04), p. 1077-1089

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In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 31, No. 5 ( 2022-05-04), p. 1077-1089

Abstract: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers ( & gt;28 g/day) with light-to-moderate drinkers (1–28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 & gt; 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose–response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype = 1.22; 95% CI, 1.14–1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920.

Type of Medium: Online Resource

ISSN: 1055-9965 , 1538-7755

URL: Article

DOI: 10.1158/1055-9965.EPI-21-1003

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2022

detail.hit.zdb_id: 2036781-8

detail.hit.zdb_id: 1153420-5

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7

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A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Aglago, Elom K. ; Kim, Andre ; Lin, Yi ; [et al.]

American Association for Cancer Research (AACR) ; 2023

In: Cancer Research Vol. 83, No. 15 ( 2023-08-01), p. 2572-2583

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In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 15 ( 2023-08-01), p. 2572-2583

Abstract: Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/0008-5472.CAN-22-3713

RVK:

XA 36000

RVK:

XA 10000

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2023

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detail.hit.zdb_id: 410466-3

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8

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Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Carreras-Torres, Robert ; Kim, Andre E. ; Lin, Yi ; [et al.]

American Association for Cancer Research (AACR) ; 2023

In: Cancer Epidemiology, Biomarkers & Prevention Vol. 32, No. 3 ( 2023-03-06), p. 315-328

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In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 32, No. 3 ( 2023-03-06), p. 315-328

Abstract: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10−8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20–1.30] compared with the other genotypes (OR & lt;1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10−8) and 8q24.23 (rs7005722, P = 2.88 × 10−8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09–1.16) compared with the other genotypes (OR & lt;1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07–1.28) compared with the other genotypes (OR & lt;1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. Impact: These findings can guide potential prevention treatments.

Type of Medium: Online Resource

ISSN: 1055-9965 , 1538-7755

URL: Article

DOI: 10.1158/1055-9965.EPI-22-0763

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2023

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9

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Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk

Tian, Yu ; Kim, Andre E ; Bien, Stephanie A ; [et al.]

Oxford University Press (OUP) ; 2022

In: JNCI: Journal of the National Cancer Institute Vol. 114, No. 8 ( 2022-08-08), p. 1135-1148

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In: JNCI: Journal of the National Cancer Institute, Oxford University Press (OUP), Vol. 114, No. 8 ( 2022-08-08), p. 1135-1148

Abstract: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2– or 3–degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2–degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P & lt; 1.2 × 10−4). Conclusion Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

Type of Medium: Online Resource

ISSN: 0027-8874 , 1460-2105

URL: Article

DOI: 10.1093/jnci/djac094

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XA 10000

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2022

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Genome-wide interaction analysis of folate for colorectal cancer risk

Bouras, Emmanouil ; Kim, Andre E. ; Lin, Yi ; [et al.]

Elsevier BV ; 2023

In: The American Journal of Clinical Nutrition ( 2023-8)

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In: The American Journal of Clinical Nutrition, Elsevier BV, ( 2023-8)

Type of Medium: Online Resource

ISSN: 0002-9165

URL: Article

DOI: 10.1016/j.ajcnut.2023.08.010

RVK:

XA 18600

Language: English

Publisher: Elsevier BV

Publication Date: 2023

detail.hit.zdb_id: 1496439-9

SSG: 12

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