Long-term multimorbidity trajectories in older adults: The role of cancer, demographics, and health behaviors.

BACKGROUND: Multimorbidity is associated with premature mortality and excess health care costs. The burden of multimorbidity is highest among patients with cancer, yet trends and determinants of multimorbidity over time are poorly understood. METHODS: Via Medicare claims linked to Cancer Prevention Study II data, group-based trajectory modeling was used to compare National Cancer Institute comorbidity index score trends for cancer survivors and older adults without a cancer history. Among cancer survivors, multinomial logistic regression analyses evaluated associations between demographics, health behaviors, and comorbidity trajectories. RESULTS: In 82,754 participants (mean age, 71.6 years [SD, 5.1 years]; 56.9% female), cancer survivors (n = 11,265) were more likely than older adults without a cancer history to experience the riskiest comorbidity trajectories: (1) steady, high comorbidity scores (remain high; odds ratio [OR], 1.36; 95% CI, 1.29-1.45), and (2) high scores that increased over time (start high and increase; OR, 1.51; 95% CI, 1.38-1.65). Cancer survivors who were physically active postdiagnosis were less likely to fall into these two trajectories (OR, 0.73; 95% CI, 0.64-0.84, remain high; OR, 0.42; 95% CI, 0.33-0.53, start high and increase) compared to inactive survivors. Cancer survivors with obesity were more likely to have a trajectory that started high and increased (OR, 2.83; 95% CI, 2.32-3.45 vs. normal weight), although being physically active offset some obesity-related risk. Cancer survivors who smoked postdiagnosis were also six times more likely to have trajectories that started high and increased (OR, 6.86; 95% CI, 4.41-10.66 vs. never smokers). CONCLUSIONS: Older cancer survivors are more likely to have multiple comorbidities accumulated at a faster pace than older adults without a history of cancer. Weight management, physical activity, and smoking avoidance postdiagnosis may attenuate that trend.

Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study.

BACKGROUND: The association of fitness with cancer risk is not clear. METHODS: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method. RESULTS: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O2⋅min-1⋅kg-1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73-0.89), colorectal (0.94, 0.90-0.99), and breast cancer (0.96, 0.92-0.99). In MR analyses, a 0.5 SD increase in genetically predicted O2⋅min-1⋅kg-1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86-0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated. DISCUSSION: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.

Diabetes mellitus in relation to colorectal tumor molecular subtypes: A pooled analysis of more than 9000 cases.

Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj : 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj : 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference  = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.

Abdominal and gluteofemoral size and risk of liver cancer: The liver cancer pooling project.

Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type-hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to <25 kg/m2 ; HR = 1.14, 95%CI: 1.07-1.21). Hip circumference, per 5 cm increase, was associated with a 9% increased PLC risk (HR = 1.09, 95%CI: 1.06-1.12), but no association remained after adjustment for waist circumference (HR = 0.99, 95%CI: 0.94-1.03). HCC and ICC results were similar. These findings suggest that excess abdominal size is associated with an increased risk of liver cancer, even among individuals considered to have a normal BMI. However, excess gluteofemoral size alone confers no increased risk. Our findings extend prior analyses, which found an association between excess adiposity and risk of liver cancer, by disentangling the separate effects of excess abdominal and gluteofemoral size through utilization of both waist and hip circumference measurements.

Meta-analysis of 16 studies of the association of alcohol with colorectal cancer.

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

The Association Between Body Mass Index and Pancreatic Cancer: Variation by Age at Body Mass Index Assessment.

Higher body mass index (BMI; weight (kg)/height (m)2) is associated with increased risk of pancreatic cancer in epidemiologic studies. However, BMI has usually been assessed at older ages, potentially underestimating the full impact of excess weight. We examined the association between BMI and pancreatic cancer mortality among 963,317 adults who were aged 30-89 years at their enrollment in Cancer Prevention Study II in 1982. During follow-up through 2014, a total of 8,354 participants died of pancreatic cancer. Hazard ratios per 5 BMI units, calculated using proportional hazards regression, declined steadily with age at BMI assessment, from 1.25 (95% confidence interval: 1.18, 1.33) in persons aged 30-49 years at enrollment to 1.13 (95% confidence interval: 1.02, 1.26) in those aged 70-89 years at enrollment (P for trend = 0.005). On the basis of a hazard ratio of 1.25 per 5 BMI units at age 45 years, we estimated that 28% of US pancreatic cancer deaths among persons born in 1970-1974 will be attributable to BMI ≥25.0-nearly twice the equivalent proportion of those born in the 1930s, a birth cohort with much lower BMI in middle age. These results suggest that BMI before age 50 years is more strongly associated with pancreatic cancer risk than BMI at older ages, and they underscore the importance of avoiding excess weight gain before middle age for preventing this highly fatal cancer.

Body Mass Index, Diabetes and Intrahepatic Cholangiocarcinoma Risk: The Liver Cancer Pooling Project and Meta-analysis.

OBJECTIVE: Obesity and diabetes are associated with an increased liver cancer risk. However, most studies have examined all primary liver cancers or hepatocellular carcinoma, with few studies evaluating intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Thus, we examined the association between obesity and diabetes and ICC risk in a pooled analysis and conducted a systematic review/meta-analysis of the literature. DESIGN: For the pooled analysis, we utilized the Liver Cancer Pooling Project, a consortium of 13 US-based, prospective cohort studies with data from 1,541,143 individuals (ICC cases n = 414). In our systematic review, we identified 14 additional studies. We then conducted a meta-analysis, combining the results from LCPP with results from the 5 prospective studies identified through September 2017. RESULTS: In the LCPP, obesity and diabetes were associated with a 62% [Hazard Ratio (HR) = 1.62, 95% Confidence Interval (CI): 1.24-2.12] and an 81% (HR = 1.81, 95% CI: 1.33-2.46) increased ICC risk, respectively. In the meta-analysis of prospectively ascertained cohorts and nested case-control studies, obesity was associated with a 49% increased ICC risk [Relative Risk (RR) = 1.49, 95% CI: 1.32-1.70; n = 4 studies; I2 = 0%]. Diabetes was associated with a 53% increased ICC risk (RR = 1.53, 95% CI: 1.31-1.78; n = 6 studies). While we noted heterogeneity between studies (I2 = 67%) for diabetes, results were consistent in subgroup analyses. Results from hospital-based case-control studies (n = 9) were mostly consistent, but these studies are potentially subject to reverse causation. CONCLUSIONS: These findings suggest that obesity and diabetes are associated with increased ICC risk, highlighting similar etiologies of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, additional prospective studies are needed to verify these associations.

Glucosamine use and risk of colorectal cancer: results from the Cancer Prevention Study II Nutrition Cohort.

PURPOSE: Use of glucosamine supplements has been associated with reduced risk of colorectal cancer (CRC) in previous studies; however, information on this association remains limited. METHODS: We examined the association between glucosamine use and CRC risk among 113,067 men and women in the Cancer Prevention Study II Nutrition Cohort. Glucosamine use was first reported in 2001 and updated every 2 years thereafter. Participants were followed from 2001 through June of 2011, during which time 1440 cases of CRC occurred. RESULTS: As has been observed in prior studies, current use of glucosamine, modeled using a time-varying exposure, was associated with lower risk of CRC (HR 0.83; 95% CI 0.71-0.97) compared to never use. However, for reasons that are unclear, this reduction in risk was observed for shorter-duration use (HR 0.68; 95% CI 0.52-0.87 for current users with ≤ 2 years use) rather than longer-duration use (HR 0.90; 95% CI 0.72-1.13 for current users with 3 to < 6 years of use; HR 0.99; 95% CI 0.76-1.29 for current users with ≥ 6 years of use). CONCLUSIONS: Further research is needed to better understand the association between glucosamine use and risk of CRC, and how this association may vary by duration of use.

Follow-up of a Large Prospective Cohort in the United States Using Linkage With Multiple State Cancer Registries.

All states in the United States now have a well-established cancer registry. Linkage with these registries may be a cost-effective method of follow-up for cancer incidence in multistate cohort studies. However, the sensitivity of linkage with the current network of state registries for detecting incident cancer diagnoses within cohort studies is not well-documented. We examined the sensitivity of registry linkage among 39,368 men and women from 23 states who enrolled in the Cancer Prevention Study-3 cohort during 2006-2009 and had the opportunity to self-report cancer diagnoses on a questionnaire in 2011. All participants provided name and birthdate, and 94% provided a complete social security number. Of 378 cancer diagnoses between enrollment and 2010 identified through self-report and verified with medical records, 338 were also detected by linkage with the 23 state cancer registries (sensitivity of 89%, 95% confidence interval (CI): 86, 92). Sensitivity was lower for hematologic cancers (69%, 95% CI: 41, 89) and melanoma (70%, 95% CI: 57, 81). After excluding hematologic cancers and melanoma, sensitivity was 94% (95% CI: 91, 97). Our results indicate that linkage with multiple cancer registries can be a sensitive method for ascertaining incident cancers, other than hematologic cancers and melanoma, in multistate cohort studies.

Alcohol intake and mortality among survivors of colorectal cancer: The Cancer Prevention Study II Nutrition Cohort.

BACKGROUND: Alcohol consumption is associated with a higher risk of colorectal cancer, but to the authors' knowledge its influence on survival after a diagnosis of colorectal cancer is unclear. The authors investigated associations between prediagnosis and postdiagnosis alcohol intake with mortality among survivors of colorectal cancer. METHODS: The authors identified 2458 men and women who were diagnosed with invasive, nonmetastatic colorectal cancer between 1992 (enrollment into the Cancer Prevention Study II Nutrition Cohort) and 2011. Alcohol consumption was self-reported at baseline and updated in 1997, 1999, 2003, and 2007. Postdiagnosis alcohol data were available for 1599 participants. RESULTS: Of the 2458 participants diagnosed with colorectal cancer, 1156 died during follow-up through 2012. Prediagnosis and postdiagnosis alcohol consumption were not found to be associated with all-cause mortality, except for an association between prediagnosis consumption of <2 drinks per day and a slightly lower risk of all-cause mortality (relative risk [RR], 0.86; 95% confidence interval [95% CI], 0.74-1.00) compared with never drinking. Alcohol use was generally not associated with colorectal cancer-specific mortality, although there was some suggestion of increased colorectal cancer-specific mortality with postdiagnosis drinking (RR, 1.27 [95% CI, 0.87-1.86] for current drinking of <2 drinks/day and RR, 1.44 [95% CI, 0.80-2.60] for current drinking of ≥2 drinks/day). CONCLUSIONS: The results of the current study do not support an association between alcohol consumption and all-cause mortality among individuals with nonmetastatic colorectal cancer. The association between postdiagnosis drinking and colorectal cancer-specific mortality should be examined in larger studies of individuals diagnosed with nonmetastatic colorectal cancer. Cancer 2017;123:2006-2013. © 2017 American Cancer Society.

Lycopene, tomato products and prostate cancer-specific mortality among men diagnosed with nonmetastatic prostate cancer in the Cancer Prevention Study II Nutrition Cohort.

While dietary lycopene and tomato products have been inversely associated with prostate cancer incidence, there is limited evidence for an association between consumption of lycopene and tomato products and prostate-cancer specific mortality (PCSM). We examined the associations of prediagnosis and postdiagnosis dietary lycopene and tomato product intake with PCSM in a large prospective cohort. This analysis included men diagnosed with nonmetastatic prostate cancer between enrollment in the Cancer Prevention Study II Nutrition Cohort in 1992 or 1993 and June 2011. Prediagnosis dietary data, collected at baseline, were available for 8,898 men, of whom 526 died of prostate cancer through 2012. Postdiagnosis dietary data, collected on follow-up surveys in 1999 and/or 2003, were available for 5,643 men, of whom 363 died of prostate cancer through 2012. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for PCSM. Neither prediagnosis nor postdiagnosis dietary lycopene intake was associated with PCSM (fourth vs. first quartile HR = 1.00, 95% CI 0.78-1.28; HR = 1.22, 95% CI 0.91-1.64, respectively). Similarly, neither prediagnosis nor postdiagnosis consumption of tomato products was associated with PCSM. Among men with high-risk cancers (T3-T4 or Gleason score 8-10, or nodal involvement), consistently reporting lycopene intake ≥ median on both postdiagnosis surveys was associated with lower PCSM (HR = 0.41, 95% CI 0.17-0.99, based on ten PCSM cases consistently ≥ median intake) compared to consistently reporting intake < median. Future studies are needed to confirm the potential inverse association of consistently high lycopene intake with PCSM among men with high-risk prostate cancers.

Circulating Leptin and Risk of Pancreatic Cancer: A Pooled Analysis From 3 Cohorts.

Adiposity is associated with pancreatic cancer; however, the underlying mechanism(s) is uncertain. Leptin is an adipokine involved in metabolic regulation, and obese individuals have higher concentrations. We conducted a pooled, nested case-control study of cohort participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and the Cancer Prevention Study II Nutrition Cohort to investigate whether prediagnostic serum leptin was associated with pancreatic cancer. A total of 731 pancreatic adenocarcinoma cases that occurred between 1986 and 2010 were included (maximum follow-up, 23 years). Incidence density-selected controls (n = 909) were matched to cases by cohort, age, sex, race, and blood draw date. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Sex-specific quintiles were based on the distribution of the controls. Overall, serum leptin was not associated with pancreatic cancer (quintile 5 vs. quintile 1: odds ratio = 1.13, 95% confidence interval: 0.75, 1.71; Ptrend = 0.38). There was a significant interaction by follow-up time (P = 0.003), such that elevated risk was apparent only during follow-up of more than 10 years after blood draw (quintile 5 vs. quintile 1: odds ratio = 2.55, 95% confidence interval: 1.23, 5.27; Ptrend = 0.004). Our results support an association between increasing leptin concentration and pancreatic cancer; however, long follow-up is necessary to observe the relationship. Subclinical disease may explain the lack of association during early follow-up.

Serum transforming growth factor-ß1 and risk of pancreatic cancer in three prospective cohort studies.

PURPOSE: Clinically evident chronic pancreatitis is a strong risk factor for pancreatic cancer. A small Japanese cohort study previously reported that pre-diagnostic serum transforming growth factor-ß1 (TGF-ß1) concentration, a potential marker of subclinical pancreatic inflammation, was associated with higher risk of pancreatic cancer. We further explored this association in a larger prospective study. METHODS: Serum TGF-ß1 concentrations were measured in pre-diagnostic samples from 729 pancreatic cancer cases and 907 matched controls from a cohort of Finnish male smokers (the Alpa-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study) and two cohorts of US men and women, the Cancer Prevention Study-II and the Prostate Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Multivariable-adjusted odds ratios (ORs) were estimated using conditional logistic regression. RESULTS: Overall, serum TGF-ß1 concentration was not associated with a clear increase in pancreatic cancer risk (OR 1.36, 95 % confidence interval (CI) 0.98-1.88 for highest vs. lowest quintile, p trend = 0.20). However, this association differed significantly by follow-up time (p = 0.02). Serum TGF-ß1 concentration was not associated with risk during the first 10 years of follow-up, but was associated with higher risk during follow-up after 10 years (OR 2.13, 95 % CI 1.23-3.68 for highest vs. lowest quintile, p trend = 0.001). During follow-up after 10 years, serum TGF-ß1 was associated with higher risk only in the ATBC cohort, although most subjects were from ATBC during this time period and statistical evidence for heterogeneity across cohorts was limited (p = 0.14). CONCLUSIONS: These results suggest that high serum TGF-ß1 may be associated with increased risk of pancreatic cancer although a long follow-up period may be needed to observe this association.

Excess Body Weight and the Risk of Second Primary Cancers Among Cancer Survivors.

Importance: Little is known about the causes of second primary cancers among individuals with a history of cancer. Descriptive studies have suggested that lifestyle factors, including excess body weight, may be important. Objective: To investigate whether excess body weight is associated with the risk of a second primary malignant neoplasm among cancer survivors. Design, Setting, and Participants: This cohort study of adults in 21 states in the US used data from the Cancer Prevention Study II Nutrition cohort, a large prospective study that invited participants to respond to a survey in 1992 and biennial surveys starting in 1997, and who were followed-up through 2017. Eligible participants included those who received a diagnosis of a first primary nonmetastatic invasive cancer between 1992 and 2015. Data analysis occurred from September 2023 to March 2024. Exposure: Body mass index (BMI), computed from self-reported height and weight at the time of the first primary cancer diagnosis (mean [SD] years to diagnosis, 1.7 [1.5] years). Main Outcome and Measures: Main outcomes included a second primary cancer or an obesity-related second cancer. Cancer diagnoses were reported on biennial surveys and verified through medical record abstraction or linkage with state cancer registries. Results: This cohort included 26 894 participants who received a diagnosis of a first nonmetastatic primary cancer (mean [SD] age at first cancer diagnosis, 72.2 [6.5] years; 15 920 male [59.2%]). At the time of first diagnosis, 11 497 participants (42.8%) had overweight and 4684 (17.2%) had obesity. During a median (IQR) follow-up time of 7.9 (3.4-13.6) years, 3749 (13.9%) participants received a diagnosis of a second primary cancer, of which 1243 (33.2%) were obesity-related second primary cancers. Compared with cancer survivors whose BMI was in the normal range (18.5 to <25), there was 15% increased risk of any second primary cancer for those who had overweight (25 to <30; adjusted hazard ratio [aHR], 1.15; 95% CI, 1.07-1.25) and a 34% increased risk for those who had obesity (BMI ≥30; aHR, 1.34; 95% CI, 1.21-1.48), with greater risk for obesity-related second primary cancers, including a 40% increased risk for those with overweight (aHR, 1.40; 95% CI, 1.22,-1.61) and a 78% increased risk for those with obesity (aHR, 1.78; 95% CI, 1.51-2.11). Conclusions and Relevance: In this cohort study of older survivors of nonmetastatic cancer, those who had overweight or obesity at the time of their first cancer diagnosis were at higher risk of developing a second cancer, especially an obesity-related second cancer. Given the high prevalence of overweight and obesity among cancer survivors, it is important to promote survivorship care guidelines recommending weight management and increase awareness of second cancers among physicians and cancer survivors.

Calcium intake and genetic variants in the calcium sensing receptor in relation to colorectal cancer mortality: an international consortium study of 18,952 patients.

Background: Research on calcium intake as well as variants in the calcium sensor receptor (CaSR) gene and their interaction in relation to CRC survival is still limited. Methods: Data from 18,952 CRC patients, were included. Associations between primarily pre-diagnostic dietary (n = 13.085), supplemental (n = 11,837), total calcium intake (n = 5970) as well as 325 single nucleotide polymorphisms (SNPs) of the CaSR gene (n = 15,734) in relation to CRC-specific and all-cause mortality were assessed using Cox proportional hazard models. Also interactions between calcium intake and variants in the CaSR gene were assessed. Results: During a median follow-up of 4.8 years (IQR 2.4-8.4), 6801 deaths occurred, of which 4194 related to CRC. For all-cause mortality, no associations were observed for the highest compared to the lowest sex- and study-specific quartile of dietary (HR 1.00, 95%CI 0.92-1.09), supplemental (HR 0.97, 95%CI 0.89-1.06) and total calcium intake (HR 0.99, 95%CI 0.88-1.11). No associations with CRC-specific mortality were observed either. Interactions were observed between supplemental calcium intake and several SNPs of the CaSR gene. Conclusion: Calcium intake was not associated with all-cause or CRC-specific mortality in CRC patients. The association between supplemental calcium intake and all-cause and CRC-specific mortality may be modified by genetic variants in the CaSR gene.

Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer.

It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue-specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue-specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.

Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival.

Background and Aims: The microbiome has long been suspected of a role in colorectal cancer (CRC) tumorigenesis. The mutational signature SBS88 mechanistically links CRC development with the strain of Escherichia coli harboring the pks island that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown. Methods: SBS88-positive CRCs were identified from targeted sequencing data from 5,292 CRCs from 17 studies and tested for their association with clinico-pathological features, oncogenic pathways, genomic characteristics and survival. Results: In total, 7.5% (398/5,292) of the CRCs were SBS88-positive, of which 98.7% (392/398) were microsatellite stable/microsatellite instability low (MSS/MSI-L), compared with 80% (3916/4894) of SBS88 negative tumors (p=1.5x10-28). Analysis of MSS/MSI-L CRCs demonstrated that SBS88 positive CRCs were associated with the distal colon (OR=1.84, 95% CI=1.40-2.42, p=1x10-5) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6x10-6) tumor sites compared with the proximal colon. The top seven recurrent somatic mutations associated with SBS88-positive CRCs demonstrated mutational contexts associated with colibactin-induced DNA damage, the strongest of which was the APC:c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3x10-80). Large copy number alterations (CNAs) including CNA loss on 14q and gains on 13q, 16q and 20p were significantly enriched in SBS88-positive CRCs. SBS88-positive CRCs were associated with better CRC-specific survival (p=0.007; hazard ratio of 0.69, 95% CI=0.52-0.90) when stratified by age, sex, study, and by stage. Conclusion: SBS88-positivity, a biomarker of colibactin-induced DNA damage, can identify a novel subtype of CRC characterized by recurrent somatic mutations, copy number alterations and better survival. These findings provide new insights for treatment and prevention strategies for this subtype of CRC.

Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing.

BACKGROUND: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer. OBJECTIVE: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing. DESIGN: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-ß, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors. RESULTS: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways. CONCLUSIONS: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation.

Epidemiologic Factors in Relation to Colorectal Cancer Risk and Survival by Genotoxic Colibactin Mutational Signature.

BACKGROUND: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88. METHODS: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases). RESULTS: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066). CONCLUSIONS: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. IMPACT: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses.

BACKGROUND: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. METHODS: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). FINDINGS: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10-5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10-5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). INTERPRETATION: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). FUNDING: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.