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  • 1
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-07-20)
    Abstract: Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI , SPZ1 , MUTYH , MAP2K4 , FETUB , and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21–0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21–1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 2
    In: JNCI: Journal of the National Cancer Institute, Oxford University Press (OUP), Vol. 113, No. 1 ( 2021-01-04), p. 38-47
    Abstract: Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. Methods We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided. Results Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10–17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10–24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10–10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10–10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10–8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes. Conclusion These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.
    Type of Medium: Online Resource
    ISSN: 0027-8874 , 1460-2105
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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    detail.hit.zdb_id: 1465951-7
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 20 ( 2020-10-15), p. 4578-4590
    Abstract: Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65–1.04)] but not BRAF-wildtype tumors [1.09 (0.97–1.22); P difference as shown in case-only analysis = 0.02] . This difference was observed in case–control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (Ptrend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. Significance: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 410466-3
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  • 4
    In: Gastroenterology, Elsevier BV, Vol. 160, No. 4 ( 2021-03), p. 1164-1178.e6
    Type of Medium: Online Resource
    ISSN: 0016-5085
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 961-961
    Abstract: Background: Consistent evidence has linked excess body fatness (EBF), typically measured in large epidemiologic studies using body mass index (BMI), with a higher risk of 13 types of cancer. Whether physical activity mitigates any of the excess risk associated with EBF is unclear—as few studies have examined the joint association between BMI and physical activity. Methods: We examined the joint association of BMI and physical activity on the risk of 12 of the 13 EBF-related cancers (excluding meningioma and including esophagus [adenocarcinoma], gastric cardia, colon and rectum, liver, gallbladder, pancreas, postmenopausal breast, corpus uteri, ovary, kidney [renal cell] , thyroid, and multiple myeloma) among 70,658 men and 72,209 postmenopausal women (median age: 63 years) without a history of cancer at study entry in the Cancer Prevention Study II Nutrition Cohort (1992-2013). Multivariable Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the individual and joint associations between BMI (kg/m2) and recreational physical activity (MET-hours/week) at study entry and first cancer incidence. Results: Between 1992-2013, 3,860 men and 9,001 women were diagnosed with an EBF-related cancer. Compared to normal weight (BMI 18.5- & lt;25 kg/m2), overweight (25- & lt;30 kg/m2) was associated with a modest increased risk of EBF-related cancer (men: HR 1.12; 95% CI: 1.04, 1.21; women: HR 1.13; 95% CI: 1.08, 1.19) and obesity (≥30 kg/m2) with a stronger risk (men: HR 1.48; 95% CI: 1.34, 1.63; women: HR 1.48; 95% CI: 1.40, 1.57). Higher levels of physical activity ( & gt;15 vs. & gt;0- & lt;7.5 MET-hrs/wk) were associated with a lower risk for EBF-related cancer among women (HR: 0.90; 95% CI: 0.85-0.95) but less so among men (HR: 0.96; 95% CI: 0.88, 1.04). Among women, there was no evidence of interaction between physical activity and BMI for the risk of EBF-related cancer (P-interaction=0.59); however, there was suggestive evidence that the excess risk associated with overweight was modestly mitigated by the highest level of physical activity (HR: 1.00; 95% CI: 0.91, 1.10). Among men, there was some evidence of an interaction between BMI and physical activity on risk (P-interaction=0.06) with the higher risk associated with overweight limited to those who were inactive (HR: 1.27; 95% CI: 1.08, 1.49). However, risk was higher for obese men irrespective of physical activity level. Conclusion: Our results suggest that higher levels of recreational physical activity may offset a small amount of the increased risk of EBF-related cancer among overweight men and women. However, physical activity does not appear to mitigate the strong effect of obesity (BMI ≥30 kg/m2) on risk of EBF-related cancers, thus reinforcing the importance of maintaining a healthy body weight even if physically active. Citation Format: Maret L. Maliniak, Susan M. Gapstur, Lauren E. McCullough, Erika Rees-Punia, Mia M. Gaudet, Caroline Y. Um, Mark A. Guinter, Elizabeth A. Fallon, Alpa V. Patel. Joint associations of physical activity and body mass index and the risk of excess body fatness-related cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 961.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 6
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Medicine & Science in Sports & Exercise Vol. 51, No. 6S ( 2019-6), p. 445-445
    In: Medicine & Science in Sports & Exercise, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. 6S ( 2019-6), p. 445-445
    Type of Medium: Online Resource
    ISSN: 1530-0315 , 0195-9131
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2031167-9
    SSG: 31
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  • 7
    In: Cancer Research Communications, American Association for Cancer Research (AACR), Vol. 2, No. 7 ( 2022-07-14), p. 653-662
    Abstract: Self-reported type 2 diabetes mellitus (T2DM) is a risk factor for many cancers, suggesting its pathology relates to carcinogenesis. We conducted a case-cohort study to examine associations of hemoglobin A1c (HbA1c) and c-peptide with cancers associated with self-reported T2DM. This study was drawn from a prospective cohort of 32,383 women and men who provided blood specimens at baseline: c-peptide and HbA1c were assessed in 3,000 randomly selected participants who were cancer-free-at-baseline and an additional 2,281 participants who were cancer-free-at-baseline and subsequently diagnosed with incident colorectal, liver, pancreatic, female breast, endometrial, ovarian, bladder, or kidney cancers. Weighted Cox regression models estimated HRs and 95% confidence intervals (CI), adjusted for covariates. c-peptide was associated with higher risk of liver cancer [per SD HR: 1.80; 95% CI: 1.32–2.46]. HbA1c was associated with higher risk of pancreatic cancer (per SD HR: 1.21; 95% CI: 1.05–1.40) and with some suggestion of higher risks for all-cancers-of-interest (per SD HR: 1.05; 95% CI: 0.99–1.11) and colorectal (per SD HR: 1.09; 95% CI: 0.98–1.20), ovarian (per SD HR: 1.18; 95% CI: 0.96–1.45) and bladder (per SD HR: 1.08; 95% CI: 0.96–1.21) cancers. Compared with no self-reported T2DM and HbA1c & lt; 6.5% (reference group), self-reported T2DM and HbA1c & lt; 6.5% (i.e., T2DM in good glycemic control) was not associated with risk of colorectal cancer, whereas it was associated with higher risks of all-cancers-of-interest combined (HR: 1.28; 95% CI: 1.01–1.62), especially for breast and endometrial cancers. Additional large, prospective studies are needed to further explore the roles of hyperglycemia, hyperinsulinemia, and related metabolic traits with T2DM-associated cancers to better understand the mechanisms underlying the self-reported T2DM-cancer association and to identify persons at higher cancer risk. Significance: The results from this study suggest that HbA1c and c-peptide, markers of hyperglycemia and hyperinsulinemia respectively, are associated with certain cancers, though people with diabetes may be at increased risk of these cancers, perhaps other than colorectal, even when their glucose is well controlled.
    Type of Medium: Online Resource
    ISSN: 2767-9764
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 8
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 31, No. 10 ( 2022-10-01), p. 1907-1918
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 31, No. 10 ( 2022-10-01), p. 1907-1918
    Abstract: Sugar-sweetened beverage (SSB) consumption may be associated with cancer mortality independent of, or indirectly through, established influences on increased body adiposity. Methods: We examined the associations of SSBs and artificially-sweetened beverages (ASB) with mortality from all-cancers combined, obesity-related cancers combined, and 20 cancer types, among men and women in the Cancer Prevention Study-II (CPS-II) prospective cohort. In 1982, 934,777 cancer-free participants provided information on usual SSB and ASB consumption. Deaths were identified through 2016. Multivariable Cox proportional hazards regression models examined associations of beverage types with cancer mortality, without and with BMI adjustment. Results: During follow-up, 135,093 CPS-II participants died from cancer. Consumption of ≥2 SSB drinks/day vs. never was not associated with all-cancer mortality, but was associated with increased risk of obesity-related cancers [HR, 1.05; 95% confidence intervals (CI), 1.01–1.08; Ptrend = 0.057], which became null after adjustment for BMI. SSBs were associated with increased mortality from colorectal (HR, 1.09; 95% CI, 1.02–1.17; Ptrend = 0.011), and kidney (HR, 1.17; 95% CI, 1.03–1.34; Ptrend = 0.056) cancers, which remained after BMI adjustment. A positive association of ASB consumption with obesity-related cancers (HR, 1.05; 95% CI, 1.01–1.08; Ptrend = 0.001) was null after controlling for BMI; however, an increased risk of pancreatic cancer was robust to BMI adjustment (HR, 1.11; 95% CI, 1.02–1.20; Ptrend  & lt; 0.008). Conclusions: SSB consumption was associated with higher mortality from certain cancers, partially mediated through obesity. Associations of ASB consumption and increased pancreatic cancer risk merit further study. Impact: Future research should consider the role of BMI in studies of sweetened beverages and cancer risk. These results should inform policy regarding sweetened beverage consumption.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    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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  • 9
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2018
    In:  Breast Cancer Research and Treatment Vol. 170, No. 3 ( 2018-8), p. 613-622
    In: Breast Cancer Research and Treatment, Springer Science and Business Media LLC, Vol. 170, No. 3 ( 2018-8), p. 613-622
    Type of Medium: Online Resource
    ISSN: 0167-6806 , 1573-7217
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2004077-5
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  • 10
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 5 ( 2020-05-01), p. 974-981
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 5 ( 2020-05-01), p. 974-981
    Abstract: Energy balance–related factors, such as body mass index (BMI), diet, and physical activity, may influence colorectal cancer etiology through interconnected metabolic pathways, but their combined influence is less clear. Methods: We used reduced rank regression to derive three energy balance scores that associate lifestyle factors with combinations of prediagnostic, circulating levels of high-sensitivity C-reactive protein (hsCRP), C-peptide, and hemoglobin A1c (HbA1c) among 2,498 participants in the Cancer Prevention Study-II Nutrition Cohort. Among 114,989 participants, we verified 2,228 colorectal cancer cases. We assessed associations of each score with colorectal cancer incidence and by tumor molecular phenotypes using Cox proportional hazards regression. Results: The derived scores comprised BMI, physical activity, screen time, and 14 food groups, and explained 5.1% to 10.5% of the variation in biomarkers. The HR and 95% confidence interval (CI) for quartile 4 versus 1 of the HbA1c+C peptide–based score and colorectal cancer was 1.30 (1.15–1.47), the hsCRP-based score was 1.35 (1.19–1.53), and the hsCRP, C-peptide, and HbA1c-based score was 1.35 (1.19–1.52). The latter score was associated with non-CIMP tumors (HRQ4vsQ1: 1.59; 95% CI: 1.17–2.16), but not CIMP-positive tumors (Pheterogeneity = 0.04). Conclusions: These results further support hypotheses that systemic biomarkers of metabolic health—inflammation and abnormal glucose homeostasis—mediate part of the relationship between several energy balance–related modifiable factors and colorectal cancer risk. Impact: Results support cancer prevention guidelines for maintaining a healthful body weight, consuming a healthful diet, and being physically active. More research is needed on these clusters of exposures with molecular phenotypes of tumors.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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