Allometric versus traditional body-shape indices and risk of colorectal cancer: a Mendelian randomization analysis.

BACKGROUND: Traditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing. METHODS: We used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank and the GIANT consortium, and from GECCO, CORECT and CCFR consortia. RESULTS: WHI was positively associated with CRC in men (OR per SD: 1.20, 95% CI: 1.03-1.39) and in women (1.15, 1.06-1.24), and similarly for colon and rectal cancer. ABSI was positively associated with colon and rectal cancer in men (1.27, 1.03-1.57; and 1.40, 1.10-1.77, respectively), and with colon cancer in women (1.20, 1.07-1.35). There was little evidence for association between HI and colon or rectal cancer. The BMI-adjusted WHR and HC showed similar associations to WHI and HI, whereas WC showed similar associations to ABSI only in women. CONCLUSIONS: This large MR study provides strong evidence for a potential causal positive association of the allometric indices ABSI and WHI with CRC in both sexes, thus establishing the association between abdominal fat and CRC without the limitations of the traditional waist size indices and independently of BMI. Among the BMI-adjusted traditional indices, WHR and HC provided equivalent associations with WHI and HI, while differences were observed between WC and ABSI.

Iron Status and Associated Factors among Canadian Women: Results from the Canadian Health Measures Survey.

BACKGROUND: Iron deficiency and overload may negatively impact women's health. There has been limited assessment of iron status and its associated factors among Canadian women. OBJECTIVES: This study investigated associations of various sociodemographic, lifestyle, medication, and dietary factors with body iron stores among pre- and postmenopausal women in Canada. METHODS: Analyses were conducted using cross-sectional, nationally representative survey and biomarker data from women aged 20-79 y (n = 6362) in the Canadian Health Measures Survey (2009-2017). Body iron stores were assessed by measuring serum concentrations of ferritin (SF). Information on potential correlates was collected during an in-home interview. Multivariable linear regression analyses were performed to evaluate associations with SF concentration, and logistic regression was used to estimate associations with iron deficiency (SF <15 µg/L) or elevated iron stores (SF >150 µg/L). RESULTS: Geometric mean SF concentrations were significantly higher in postmenopausal than in premenopausal women (73.2 versus 33.8 µg/L; P < 0.001). The prevalence of iron deficiency among pre- and postmenopausal women was 16.0% and 4.0%, respectively, whereas that of elevated iron stores was 2.7% and 21.0%, respectively. After simultaneous adjustment for multiple factors, including high-sensitivity CRP (inflammation marker), we found that age, East/Southeast Asian (versus White) race/ethnicity, alcohol, and red meat consumption were positively associated with SF concentration among pre- and postmenopausal women. In addition, aspirin use and dairy consumption were inversely associated with SF concentration among postmenopausal women only. Similar patterns were observed for associations with elevated iron stores among postmenopausal women, whereas higher grain consumption was associated with an increased prevalence of iron deficiency among premenopausal women. CONCLUSIONS: Sociodemographic, lifestyle, medication, and dietary factors are correlated with iron status determined by SF concentration among Canadian women. The findings may have implications for intervention strategies aimed at optimizing body iron stores in pre- and postmenopausal women.

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

Risk factors for early-onset colorectal cancer: a population-based case-control study in Ontario, Canada.

PURPOSE: There has been an alarming increase in colorectal cancer (CRC) incidence among young adults aged < 50 years, and factors driving this upward trend are unknown. This study investigated associations between various medical, lifestyle, and dietary factors and risk of early-onset CRC (EO-CRC). METHODS: A population-based case-control study was conducted in Ontario, Canada during 2018-2019. EO-CRC cases aged 20-49 years (n = 175) were identified from the Ontario Cancer Registry; sex- and age group-matched controls (n = 253) were recruited through random digit dialing. Data on potential a priori risk factors were collected using a web-based self-reported questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression. RESULTS: Family history of CRC in a first- or second-degree relative (OR 2.37; 95% CI 1.47-3.84), longer sedentary time (≥ 10 vs. < 5 h/day, OR 1.93; 95% CI 1.02-3.65), greater consumption of sugary drinks (≥ 7 vs. < 1 drinks/week, OR 2.99; 95% CI 1.57-5.68), and a more Westernized dietary pattern (quartile 4 vs. 1, OR 1.92; 95% CI 1.01-3.66) were each associated with an increased risk of EO-CRC. Conversely, calcium supplement use (OR 0.53; 95% CI 0.31-0.92), history of allergy or asthma (OR 0.62; 95% CI 0.39-0.98), and greater parity in females (≥ 3 vs. nulliparity, OR 0.29; 95% CI 0.11-0.76) were each associated with a reduced risk. CONCLUSION: Modifiable factors, particularly sedentary behavior and unhealthy diet including sugary drink consumption, may be associated with EO-CRC risk. Our findings, if replicated, may help inform prevention strategies targeted at younger persons.

Iron intake, oxidative stress-related genes and breast cancer risk.

Iron has been suggested to contribute to breast cancer development through oxidative stress generation. Our study investigated associations between iron intake and breast cancer risk, overall and by menopausal and estrogen receptor/progesterone receptor (ER/PR) status, and modification by oxidative stress-related genetic polymorphisms (MnSOD, GSTM1 and GSTT1). A population-based case-control study (3,030 cases and 3,402 controls) was conducted in Ontario, Canada. Iron intake (total, dietary, supplemental, heme, nonheme) was assessed using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. Interactions between iron intake and genotypes were assessed among 1,696 cases and 1,761 controls providing DNA. Overall, no associations were observed between iron intake and breast cancer risk. Among premenopausal women, total, dietary and dietary nonheme iron were positively associated with ER-/PR- breast cancer risk (all ptrend < 0.05). Among postmenopausal women, supplemental iron was associated with reduced breast cancer risk (OR>18 vs. 0 mg/day = 0.68, 95% CI: 0.51-0.91), and dietary heme iron was associated with an increased risk, particularly the ER-/PR- subtype (ORhighest vs. lowest quintile = 1.69, 95% CI: 1.16-2.47; ptrend = 0.02). Furthermore, GSTT1 and combined GSTM1/GSTT1 polymorphisms modified some of the associations. For example, higher dietary iron was most strongly associated with increased breast cancer risk among women with GSTT1 deletion or GSTM1/GSTT1 double deletions (pinteraction < 0.05). Findings suggest that iron intake may have different effects on breast cancer risk according to menopausal and hormone receptor status, as well as genotypes affecting antioxidant capacity.

DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility.

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

Potential impact of family history-based screening guidelines on the detection of early-onset colorectal cancer.

BACKGROUND: Initiating screening at an earlier age based on cancer family history is one of the primary recommended strategies for the prevention and detection of early-onset colorectal cancer (EOCRC), but data supporting the effectiveness of this approach are limited. The authors assessed the performance of family history-based guidelines for identifying individuals with EOCRC. METHODS: The authors conducted a population-based, case-control study of individuals aged 40 to 49 years with (2473 individuals) and without (772 individuals) incident CRC in the Colon Cancer Family Registry from 1998 through 2007. They estimated the sensitivity and specificity of family history-based criteria jointly recommended by the American Cancer Society, the US Multi-Society Task Force on CRC, and the American College of Radiology in 2008 for early screening, and the age at which each participant could have been recommended screening initiation if these criteria had been applied. RESULTS: Family history-based early screening criteria were met by approximately 25% of cases (614 of 2473 cases) and 10% of controls (74 of 772 controls), with a sensitivity of 25% and a specificity of 90% for identifying EOCRC cases aged 40 to 49 years. Among 614 individuals meeting early screening criteria, 98.4% could have been recommended screening initiation at an age younger than the observed age of diagnosis. CONCLUSIONS: Of CRC cases aged 40 to 49 years, 1 in 4 met family history-based early screening criteria, and nearly all cases who met these criteria could have had CRC diagnosed earlier (or possibly even prevented) if earlier screening had been implemented as per family history-based guidelines. Additional strategies are needed to improve the detection and prevention of EOCRC for individuals not meeting family history criteria for early screening.

Trajectories of physical activity, from young adulthood to older adulthood, and pancreatic cancer risk; a population-based case-control study in Ontario, Canada.

BACKGROUND: There is inconsistent evidence on the association between physical activity and pancreatic cancer risk and few studies have investigated early life or life-course physical activity. The objective of this study was to evaluate the association between trajectories of physical activity across the life-course and pancreatic cancer risk. METHODS: A population-based case-control study was conducted (2011-2013) using cases (n = 315) from the Ontario Pancreas Cancer Study and controls (n = 1254) from the Ontario Cancer Risk Factor Study. Self-reported recall of moderate and vigorous physical activity was measured at three time points: young adulthood (20s-30s), mid-adulthood (40s-50s) and older-adulthood (1 year prior to questionnaire completion). Physical activity trajectories were identified using latent class analysis. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression adjusted for covariates: age, sex, race, alcohol, smoking, vegetable, fruit and meat consumption, and family history of pancreatic cancer. RESULTS: Six life-course physical activity trajectories were identified: inactive at all ages (41.2%), low activity at all ages (31.9%), increasingly active (3.6%), high activity in young adulthood with substantial decrease (13.0%), high activity in young adulthood with slight decrease (5.0%), and persistent high activity (5.3%). Compared to the inactive at all ages trajectory, the associations between each trajectory and pancreatic cancer after confounder adjustment were: low activity at all ages (OR: 1.11; 95% CI: 0.75, 1.66), increasingly active (OR: 1.11; 95% CI: 0.56, 2.21), high activity in young adulthood with substantial decrease in older adulthood (OR: 0.76; 95% CI: 0.47, 1.23), high activity in young adulthood with slight decrease in older adulthood (OR: 0.98; 95% CI: 0.62, 1.53), and persistently high activity (OR: 1.50; 95% CI: 0.86, 2.62). When time periods were evaluated separately, the OR for the association between high moderate activity in the 20s-30s and pancreatic cancer was 0.89 (95% CI: 0.64, 1.25) and some sex differences were observed. CONCLUSION: Distinct life-course physical activity trajectories were identified, but there was no evidence that any of the trajectories were associated with pancreatic cancer. Future studies with larger sample sizes are needed to understand the associations between physical activity trajectories over the life-course and pancreatic cancer risk.

Trajectories of body mass index, from adolescence to older adulthood, and pancreatic cancer risk; a population-based case-control study in Ontario, Canada.

PURPOSE: Pancreatic cancer has the highest fatality rate of all cancers. Adulthood obesity is an established risk factor for pancreatic cancer; however, life-course obesity is not well understood. The aim of this study was to evaluate the association between body mass index (BMI) trajectories throughout the life-course and pancreatic cancer risk. METHODS: A population-based case-control study was conducted (2011-2013) in Ontario, Canada. Cases were recruited from the Ontario pancreas cancer study (n = 310) and controls from the Ontario cancer risk factor study (n = 1258). Questionnaires captured self-reported height and weight at four timepoints (adolescence, 20 s, 30-40 s, 50-60 s). BMI trajectories were identified using latent class growth mixture modeling. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression. RESULTS: Five BMI trajectories were identified: stable-normal weight (38.9%), progressively overweight (42.2%), persistent overweight (12.6%), progressive obesity (4.2%), and persistent obesity (2.1%). The persistent overweight (OR = 1.55; 95% CI 1.02, 2.39) and progressive obesity trajectories (OR = 1.49; 95% CI 0.77, 2.87) compared to stable-normal weight were associated with increased odds of pancreatic cancer. When BMI was evaluated separately the strongest associations with pancreatic cancer emerged in young and mid-adulthood. CONCLUSION: BMI trajectories characterized by overweight in early adulthood were associated with increased pancreatic cancer risk suggesting a life-course approach to disease risk.

Iron intake, body iron status, and risk of breast cancer: a systematic review and meta-analysis.

BACKGROUND: Iron has been shown to promote breast carcinogenesis in animal models through generation of oxidative stress and interaction with estrogen. Heme iron, which is found exclusively in animal-sourced foods, is suggested to have a more detrimental effect. Epidemiological evidence of the association between iron and breast cancer risk remains inconclusive and has not been comprehensively summarized. This systematic review and meta-analysis evaluated associations between both iron intake and body iron status and breast cancer risk. METHODS: Four electronic databases (MEDLINE, EMBASE, CINAHL, and Scopus) were searched up to December 2018 for studies assessing iron intake and/or biomarkers of iron status in relation to breast cancer risk. Using random-effects meta-analyses, pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated comparing the highest vs. lowest category of each iron measure. Dose-response meta-analyses were also performed to investigate linear and nonlinear associations. RESULTS: A total of 27 studies were included in the review, of which 23 were eligible for meta-analysis of one or more iron intake/status measures. Comparing the highest vs. lowest category, heme iron intake was significantly associated with increased breast cancer risk, with a pooled RR of 1.12 (95% CI: 1.04-1.22), whereas no associations were found for dietary (1.01, 95% CI: 0.89-1.15), supplemental (1.02, 95% CI: 0.91-1.13), or total (0.97, 95% CI: 0.82-1.14) iron intake. Associations of iron status indicators with breast cancer risk were generally in the positive direction; however, a significant pooled RR was found only for serum/plasma levels (highest vs. lowest) of iron (1.22, 95% CI: 1.01-1.47), but not for ferritin (1.13, 95% CI: 0.78-1.62), transferrin saturation (1.16, 95% CI: 0.91-1.47), or total iron-binding capacity (1.10, 95% CI: 0.97-1.25). In addition, a nonlinear dose-response was observed for heme iron intake and serum iron (both Pnonlinearity < 0.05). CONCLUSIONS: Heme iron intake and serum iron levels may be positively associated with breast cancer risk. Although associations were modest, these findings may have public health implications given the widespread consumption of (heme) iron-rich foods. In light of methodological and research gaps identified, further research is warranted to better elucidate the relationship between iron and breast cancer risk.

Effect of Dietary Flaxseed Intake on Circulating Sex Hormone Levels among Postmenopausal Women: A Randomized Controlled Intervention Trial.

Lignan intake, and its richest food source, flaxseed, have been associated with reduced breast cancer risk. Endogenous sex hormones, such as estrogens, play a role in breast cancer development, and lignans may alter these sex hormone levels. To assess the effect of flaxseed on circulating sex hormones, a randomized controlled trial was conducted among 99 postmenopausal women in Toronto, Canada. The intervention arm consumed 2 tablespoons (15 g) of ground flaxseed daily for 7 weeks; the control arm maintained usual diet. Baseline and week 7 concentrations of 14 serum sex hormones were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassay, and serum enterolignans (lignan biomarker) using LC-MS/MS. Intervention effects on sex hormone levels were assessed using analysis of covariance. Serum enterolignans increased among the flaxseed arm (+516%). Women consuming flaxseed (vs. controls) had increased serum 2-hydroxyestrone [treatment effect ratio (TER) = 1.54; 95% CI: 1.18-2.00] and 2:16α-hydroxyestrone ratio (TER =1.54; 95% CI: 1.15-2.06); effects on other hormones were not statistically significant. Within the flaxseed arm, change in enterolignan level was positively correlated with changes in 2-hydroxyestrone and 2:16α-hydroxyestrone ratio, and negatively with prolactin. Findings suggest flaxseed affects certain circulating sex hormone levels with possible implications for future breast cancer prevention research.

Symptom Severity and Quality of Life Among Long-term Colorectal Cancer Survivors Compared With Matched Control Subjects: A Population-Based Study.

BACKGROUND: Data are lacking regarding physical functioning, psychological well-being, and quality of life among colorectal cancer survivors >10 years postdiagnosis. OBJECTIVE: The purpose of this study was to examine self-reported physical functioning, quality of life, and psychological well-being in long-term colorectal cancer survivors compared with age- and sex-matched unaffected control subjects. DESIGN: Participants completed a cross-sectional survey. SETTINGS: The colorectal cancer survivors and unaffected control subjects were recruited from the Ontario Familial Colorectal Cancer Registry. PATIENTS: A population-based sample of colorectal cancer survivors (N = 296) and their age- and sex-matched unaffected control subjects (N = 255) were included. Survivors were, on average, 15 years postdiagnosis. MAIN OUTCOME MEASURES: Quality of life was measured with the Functional Assessment of Cancer Therapy-General scale, bowel dysfunction with the Memorial Sloan-Kettering Cancer Center scale, urinary dysfunction with the International Consultation on Incontinence Questionnaire-Short Form, fatigue with the Functional Assessment of Chronic Illness Therapy-Fatigue scale, and depression with the Center for Epidemiologic Studies-Depression scale. RESULTS: In linear mixed-model analyses adjusting for income, education, race, and comorbid medical conditions, survivors reported good emotional, functional, physical, and overall quality of life, comparable to control subjects. Fatigue and urinary functioning did not differ significantly between survivors and control subjects. Survivors reported significantly higher social quality of life and lower depression compared with unaffected control subjects. The only area where survivors reported significantly worse deficits was in bowel dysfunction, but the magnitude of differences was relatively small. LIMITATIONS: Generalizability is limited by moderately low participation rates. Findings are likely biased toward healthy participants. No baseline assessment was available to examine change in outcomes over time. CONCLUSIONS: Long-term colorectal cancer survivors appear to have comparable quality of life and, in some areas, better well-being than their unaffected peers. Bowel dysfunction may continue to be an ongoing issue even 15 years after colorectal cancer diagnosis. Overall quality of life can be expected to be good in this group of older survivors. See Video Abstract at http://links.lww.com/DCR/A476.

Cervical cancer screening uptake among HIV-positive women in Ontario, Canada: A population-based retrospective cohort study.

Cervical cancer caused by oncogenic types of the human papillomavirus (HPV) is of concern among HIV-positive women due to impairment of immune responses required to control HPV infection. Our objectives were to describe patterns of cervical cancer screening using Pap cytology testing among HIV-positive women in Ontario, Canada from 2008 to 2013 and to identify factors associated with adequate screening. We conducted a retrospective, population-based cohort study among screen-eligible HIV-positive women using provincial administrative health data. We estimated annual proportions tested and reported these with 95% confidence intervals (CI). Next, using person-years as the unit of analysis, we identified factors associated with annual Pap testing using log-binomial regression. A total of 2271 women were followed over 10,697 person-years. In 2008, 34.0% (95%CI 31.1-37.0%) had a Pap test. By 2013, the proportion of HIV-positive women tested was 25.9% (95%CI 23.6-28.2%). Women who were most likely to undergo testing were younger, were immigrants from countries with generalized HIV epidemics, lived in the highest income neighbourhoods, had a female primary care physician, had two or more encounters per year with an infectious disease or internal medicine specialist, and had greater comorbidity. Nearly three in four HIV-positive women were under-screened despite all having universal insurance for medically-necessary services. Annual Pap testing decreased following the 2011-2013 release of new guidelines for a lengthened screen interval for average risk women and a billing disincentive. Clinic-based intervention such as physician alerts or reminders may be needed to improve screening coverage among HIV-positive women.

Long-term weight loss after colorectal cancer diagnosis is associated with lower survival: The Colon Cancer Family Registry.

BACKGROUND: Body weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long-term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival. METHODS: CRC cases diagnosed from 1997 to 2008 were identified through 4 population-based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow-up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC-specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti-inflammatory drug use, smoking, time between diagnosis and enrollment, and study site. RESULTS: At the 5-year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median -4 kg) weight. Over a median of 5.1 years of subsequent follow-up (range, 0.3-9.9 years), 344 participants died (91 of CRC). Long-term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07-1.21) and CRC-specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13-1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs ≤5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight). CONCLUSIONS: Weight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long-term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017;123:4701-4708. © 2017 American Cancer Society.

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Genome-wide diet-gene interaction analyses for risk of colorectal cancer.

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.

BRM polymorphisms, pancreatic cancer risk and survival.

Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM-1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex. BRM suppression can be reversed pharmacologically.(1) Our group and others have reported associations with lung, head and neck, hepatocellular cancer risk,(1-3) and with lung and esophageal cancer prognosis (ASCO 2013; abstract 11057 & 4077). Herein, we assessed risk and survival associations with pancreatic cancer. A provincial population-based case-control study was conducted with 623 histologically confirmed pancreatic adenocarcinoma cases and 1,192 age/gender distribution-matched controls.(4) Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Median age was 65 y; 52% were male; Stage I (8%), II (55%), III (14%), IV (23%); 53% after curative resection, 79% after chemotherapy; and 83% had died. In the risk analysis, adjusted odds ratios (aOR) were 1.01 (95% CI: 0.1-2.0) and 0.96 (95% CI: 0.7-1.3) for the homozygotes of BRM-741 and BRM-1321, respectively; aOR of double-homozygotes was 1.11 (95% CI: 0.80-1.53), compared to the double-wildtype. For the survival analysis, adjusted hazard ratios (aHR) were 2.19 (95% CI: 1.9-2.5) for BRM-741 and 1.94 (95% CI: 1.7-2.2) for BRM-1321, per unit increase in variant alleles. Compared with the double-wildtype, aHR for carrying no, one, and two double-homozygotes were 2.14 (95% CI: 1.6-2.8), 4.17 (95% CI: 3.0-5.7), 8.03 (95% CI: 5.7-11.4), respectively. In conclusion, two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival.

Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH.

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first- and 3,255 second-degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7-97) and ovarian cancer 17 (2.4-115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7-13); hepatobiliary cancer 4.5 (2.7-7.5); endometrial cancer 2.1 (1.1-3.9) and breast cancer 1.4 (1.0-2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5-77%) for males and 8% (2-33%) for females and ovarian cancer 14% (2-65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4-7%) for males and 2.3% (1.7-3.3%) for females; hepatobiliary cancer 3% (2-5%) for males and 1.4% (0.8-2.3%) for females; endometrial cancer 3% (2%-6%) and breast cancer 11% (8-16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.

CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT. METHODS: We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test. RESULTS: The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 × 10(-9)). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 × 10(-5) (alpha threshold=3.1 × 10(-4)). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively. CONCLUSIONS: Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.

Breast cancer survival among young women: a review of the role of modifiable lifestyle factors.

Almost 7% of breast cancers are diagnosed among women age 40 years and younger in Western populations. Clinical outcomes among young women are worse. Early age-of-onset increases the risk of contralateral breast cancer, local and distant recurrence, and subsequent mortality. Breast cancers in young women (BCYW) are more likely to present with triple-negative (TNBC), TP53-positive, and HER-2 over-expressing tumors than among older women. However, despite these known differences in breast cancer outcomes and tumor subtypes, there is limited understanding of the basic biology, epidemiology, and optimal therapeutic strategies for BCYW. Several modifiable lifestyle factors associated with reduced risk of developing breast cancer have also been implicated in improved prognosis among breast cancer survivors of all ages. Given the treatment-related toxicities and the extended window for late effects, long-term lifestyle modifications potentially offer significant benefits to BCYW. In this review, we propose a model identifying three main areas of lifestyle factors (energy imbalance, inflammation, and dietary nutrient adequacy) that may influence survival in BCYW. In addition, we provide a summary of mechanisms of action and a synthesis of previous research on each of these topics.