Search

Background: Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair genes, which lead to high microsatellite instability and frameshift mutations at coding mononucleotide repeats in the genome. Recurrent frameshift mutations in these regions are thought to play a central role in the increased risk of various cancers, but no biomarkers are currently available for the surveillance of high microsatellite instability-associated cancers., Methods: A frameshift mutation-based biomarker panel was developed and validated by targeted next-generation sequencing of supernatant DNA from cultured high microsatellite instability colorectal cancer cells. This panel supported selection of 122 frameshift mutation targets as potential biomarkers. This biomarker panel was then tested using matched tumor, adjacent normal tissue, and buffy coat samples (53 samples) and blood-derived cell-free DNA (cfDNA) (38 samples) obtained from 45 high microsatellite instability and mismatch repair-deficient patients. We also sequenced cfDNA from 84 healthy participants to assess background noise., Results: Recurrent frameshift mutations at coding mononucleotide repeats were detectable not only in tumors but also in cfDNA from high microsatellite instability and mismatch repair-deficient patients, including a Lynch syndrome carrier, with a varying range of target detection (up to 85.2%), whereas they were virtually undetectable in healthy participants. Receiver operating characteristic curve analysis showed high sensitivity and specificity (area under the curve = 0.94) of the investigated panel., Conclusions: We demonstrated that frameshift mutations can be detected in cfDNA from high microsatellite instability and mismatch repair-deficient patients and asymptomatic carriers. The 122-target frameshift mutation panel described here has promise as a tool for improved surveillance of high microsatellite instability and mismatch repair-deficient patients, with the potential to reduce the frequency of invasive screening methods for this high-cancer-risk cohort., (Published by Oxford University Press 2024.)

Background: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk., Methods: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants., Results: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4)., Conclusion: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: 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., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk., Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided., Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0., Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Postmenopausal hormone therapy use has been associated with lower colorectal cancer risk in observational studies. However, the role of endogenous sex hormones in colorectal cancer development in postmenopausal women is uncertain., Methods: The relation of colorectal cancer risk with circulating levels of estradiol, estrone, free (bioactive) estradiol, progesterone and sex hormone-binding globulin (SHBG) was determined in a nested case-control study of 1203 postmenopausal women (401 case patients and 802 age and race/ethnicity-matched control patients) enrolled in the Women's Health Initiative Clinical Trial (WHI-CT) who were not assigned to the estrogen-alone or combined estrogen plus progestin intervention groups. We used multivariable-adjusted conditional logistic regression models that included established colorectal cancer risk factors. All statistical tests were two-sided., Results: Comparing extreme quartiles, estrone (odds ratio [OR]q4-q1 = 0.44, 95% confidence interval [CI] = 0.28 to 0.68, P trend = .001), free estradiol (ORq4-q1 = 0.43, 95% CI = 0.27 to 0.69, P trend ≤ .0001), and total estradiol (ORq4-q1 = 0.58, 95% CI = 0.38 to 0.90, P trend = .08) were inversely associated with colorectal cancer risk. SHBG levels were positively associated with colorectal cancer development (OR[q4-q1] = 2.30, 95% CI = 1.51 to 3.51, P trend ≤ .0001); this association strengthened after further adjustment for estradiol and estrone (ORq4-q1 = 2.50, 95% CI = 1.59 to 3.92, P trend < .0001). Progesterone was not associated with colorectal cancer risk., Conclusion: Endogenous estrogen levels were inversely, and SHBG levels positively, associated with colorectal cancer risk, even after control for several colorectal cancer risk factors. These results suggest that endogenous estrogens may confer protection against colorectal tumorigenesis among postmenopausal women., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 causes a high risk of colorectal and other cancers (Lynch Syndrome). Use of aspirin has been shown to be associated with a reduced risk of colorectal cancer for the general population as well as for MMR gene mutation carriers. The aim of this study was to determine whether use of aspirin and ibuprofen in a nontrial setting is associated with the risk of colorectal cancer risk for MMR gene mutation carriers., Methods: We included 1858 participants in the Colon Cancer Family Registry who had been found to have a pathogenic germline mutation in a MMR gene (carriers). We used weighted Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided., Results: A total of 714 carriers (38%) were diagnosed with colorectal cancer at a mean age of 42.4 (standard deviation 10.6) years. A reduced risk of colorectal cancer was associated with aspirin use (for 1 month to 4.9 years: HR = 0.49, 95% CI = 0.27 to 0.90, P = .02; for ≥5 years: HR = 0.25, 95% CI = 0.10 to 0.62, P = .003) and ibuprofen use (for 1 month to 4.9 years: HR = 0.38, 95% CI = 0.18 to 0.79, P = .009; for ≥5 years: HR = 0.26, 95% CI = 0.10 to 0.69, P = .007), compared with less than one month of use., Conclusion: Our results provide additional evidence that, for MMR gene mutation carriers, use of aspirin and ibuprofen might be effective in reducing their high risk of colorectal cancer., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Genetic association studies have traditionally focused on associations between individual single nucleotide polymorphisms (SNPs) and disease. Standard analysis ignores interactions between multiple SNPs and environmental exposures explaining a small portion of disease heritability: the often-cited issue of "missing heritability.", Methods: We present a novel three-step analytic framework for modeling gene-environment interactions (GEIs) between an angiogenesis candidate-gene pathway and three lifestyle exposures (dietary protein, smoking, and alcohol consumption) on colon cancer risk and survival. Logic regression was used to summarize the gene-pathway effects, and GEIs were modeled using logistic regression and Cox proportional hazards models. We analyzed data from 1541 colon cancer case patients and 1934 control subjects in the Diet, Activity and Lifestyle as a Risk Factor for Colon Cancer Study., Results: We identified five statistically significant GEIs for colon cancer risk. For risk interaction, odds ratios (ORINT) and 95% confidence intervals (CIs) were FLT1(rs678714) and BMP4(rs17563) and smoking (ORINT = 1.64, 95% CI = 1.11 to 2.41 and ORINT = 1.60, 95% CI = 1.10 to 2.32, respectively); FLT1(rs2387632 OR rs9513070) and protein intake (ORINT = 1.69, 95% CI = 1.03 to 2.77); KDR(rs6838752) and TLR2(rs3804099) and alcohol (ORINT = 1.53, 95% CI = 1.10 to 2.13 and ORINT = 1.59, 95% CI = 1.05 to 2.38, respectively). Three GEIs between TNF, BMP1, and BMPR2 genes and the three exposures were statistically significant at the 5% level in relation to colon cancer survival but not after multiple-testing adjustment., Conclusions: Adopting a comprehensive biologically informed candidate-pathway approach identified GEI effects on colon cancer. Findings may have important implications for public health and personalized medicine targeting prevention and therapeutic strategies. Findings from this study need to be validated in other studies., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Most cancers occur more frequently in men. Numerous explanations for this excess risk have been proposed, yet no study has quantified the degree to which height explains the sex difference even though greater height has been associated with increased risk for many cancers., Methods: During the period from 2000 to 2002, 65308 volunteers aged 50 to 76 years were recruited to the Vitamins And Lifestyle (VITAL) study. Cancers of shared anatomic sites (n = 3466) were prospectively identified through 2009 through the Surveillance, Epidemiology, and End Results cancer registry. Age- and race-adjusted hazard ratios (HRs) for the associations between sex and incident cancers were estimated using Cox proportional hazards models, with and without adjustment for height and height squared as measures of body size., Results: Men had a 55% increased risk of cancer at shared sites (HR = 1.55; 95% confidence interval [CI] = 1.45 to 1.66). When height was accounted for, 33.8% (95% CI = 10.2% to 57.3%) of the excess risk for men was explained by the height differences between sexes. The proportion mediated by height was 90.9%, 57.3%, and 49.6% for kidney, melanoma, and hematologic malignancies, respectively, with little evidence that height mediates the sex difference for gastrointestinal tract, lung, and bladder cancers. For comparison, more than 35 lifestyle and medical risk factors only explained 23.1% of the sex difference in cancer risk at shared sites., Conclusions: Height is an important explanatory factor for the excess risk for men for many shared-site cancers. This suggests that some of the excess risk is due to factors associated with height (eg, number of susceptible cells in a specific organ or growth-influencing exposures in childhood).

Background: Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer., Methods: We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37 399 participants in a population-based cohort study (the Iowa Women's Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs)., Results: Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation-positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation-positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation-negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27)., Conclusions: In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation-positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.

Background: Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%-20% of colorectal tumors display microsatellite instability (MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status., Methods: The study included 1794 case subjects with incident colorectal cancer who were identified through population-based cancer registries and 2684 of their unaffected sex-matched siblings as control subjects. Recent body mass index (BMI), BMI at age 20 years, and adult weight change were derived from self-reports of height and weight. Tumor MSI status, assessed at as many as 10 markers, was obtained for 69.7% of the case subjects and classified as microsatellite (MS)-stable (0% of markers unstable; n = 913), MSI-low (>0% but <30% of markers unstable; n = 149), or MSI-high (> or =30% of markers unstable; n = 188). Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided., Results: Recent BMI, modeled in 5 kg/m(2) increments, was positively associated with risk of colorectal cancer for men and women combined (OR = 1.24; 95% CI = 1.15 to 1.34), for women only (OR = 1.20; 95% CI = 1.10 to 1.32), and for men only (OR = 1.30; 95% CI = 1.15 to 1.47). There was no interaction with sex (P = .22). Recent BMI, per 5 kg/m(2), was positively associated with the risk of MS-stable (OR = 1.38; 95% CI = 1.24 to 1.54) and MSI-low (OR = 1.33; 95% CI = 1.04 to 1.72) colorectal tumors, but not with the risk of MSI-high tumors (OR = 1.05; 95% CI = 0.84 to 1.31)., Conclusion: The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status.

Research methods for biomarker evaluation lag behind those for evaluating therapeutic treatments. Although a phased approach to development of biomarkers exists and guidelines are available for reporting study results, a coherent and comprehensive set of guidelines for study design has not been delineated. We describe a nested case-control study design that involves prospective collection of specimens before outcome ascertainment from a study cohort that is relevant to the clinical application. The biomarker is assayed in a blinded fashion on specimens from randomly selected case patients and control subjects in the study cohort. We separately describe aspects of the design that relate to the clinical context, biomarker performance criteria, the biomarker test, and study size. The design can be applied to studies of biomarkers intended for use in disease diagnosis, screening, or prognosis. Common biases that pervade the biomarker research literature would be eliminated if these rigorous standards were followed.

A shortage of credible information exists on practical dietary and physical activity patterns that have potential to reverse the national obesity epidemic and reduce the risk of major cancers and other chronic diseases. Securing such information is a challenging task, and there is considerable diversity of opinion concerning related research designs and priorities. Here, we put forward some perspectives on useful methodology and infrastructure developments for progress in this important area, and we list high-priority research topics in the areas of 1) assessment of nutrient intake and energy expenditure; 2) development of intermediate outcome biomarkers; 3) enhancement of cohort and cross-cultural studies; and 4) criteria for and development of full-scale nutrition and physical activity intervention trials.

Background: Studies in animals have suggested that calcium may reduce the risk of colorectal cancer. However, results from epidemiologic studies of intake of calcium or dairy foods and colorectal cancer risk have been inconclusive., Methods: We pooled the primary data from 10 cohort studies in five countries that assessed usual dietary intake by using a validated food frequency questionnaire at baseline. For most studies, follow-up was extended beyond that in the original publication. The studies included 534 536 individuals, among whom 4992 incident cases of colorectal cancer were diagnosed between 6 and 16 years of follow-up. Pooled multivariable relative risks for categories of milk intake and quintiles of calcium intake and 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided., Results: Milk intake was related to a reduced risk of colorectal cancer. Compared with the lowest category of intake (<70 g/day), relative risks of colorectal cancer for increasing categories (70-174, 175-249, and > or =250 g/day) of milk intake were 0.94 (95% CI = 0.86 to 1.02), 0.88 (95% CI = 0.81 to 0.96), and 0.85 (95% CI = 0.78 to 0.94), respectively (P(trend)<.001). Calcium intake was also inversely related to the risk of colorectal cancer. The relative risk for the highest versus the lowest quintile of intake was 0.86 (95% CI = 0.78 to 0.95; P(trend) =.02) for dietary calcium and 0.78 (95% CI = 0.69 to 0.88; P(trend)<.001) for total calcium (combining dietary and supplemental sources). These results were consistent across studies and sex. The inverse association for milk was limited to cancers of the distal colon (P(trend)<.001) and rectum (P(trend) =.02)., Conclusion: Higher consumption of milk and calcium is associated with a lower risk of colorectal cancer.

Screening sigmoidoscopy is associated with a reduction in both the incidence and mortality of colorectal cancer. Although current guidelines recommend sigmoidoscopy screening every 5 years, the duration of risk reduction is not known. We conducted a population-based case-control study to examine the association between sigmoidoscopy screening and colorectal cancer incidence. We collected information on screening history and risk factors from case patients with distal (n = 1026) and proximal (n = 642) colorectal cancer and from 1294 control subjects from October 1998 through February 2002. Screening sigmoidoscopy was associated with a statistically significant reduction in the incidence of distal colorectal cancer (odds ratio [OR] = 0.24, 95% confidence interval [CI] = 0.17 to 0.33). These reductions were sustained for up to 16 years with little attenuation. We also observed strong inverse associations between cancer incidence and sigmoidoscopy in analyses that included subjects with symptom-related tests. Current recommendations regarding the frequency of sigmoidoscopy screening may be unnecessarily aggressive.

Background: Breast-feeding is well known to have a protective effect against infection in infants. Although the long-term effects of breast-feeding on childhood cancer have not been studied extensively, a protective effect against childhood Hodgkin's disease and lymphoma has been suggested previously from small investigations. In this study, we tested the hypothesis that breast-feeding decreases the risk of childhood acute leukemia., Methods: A total of 1744 children with acute lymphoblastic leukemia (ALL) and 1879 matched control subjects, aged 1-14 years, and 456 children with acute myeloid leukemia (AML) and 539 matched control subjects, aged 1-17 years, were included in the analysis. Information regarding breast-feeding was obtained through telephone interviews with mothers. All leukemias combined, histologic type of leukemia (ALL versus AML), immunophenotype of ALL (early pre-B cell, pre-B cell, or T cell), and morphology of AML were assessed separately in the data analysis., Results: Ever having breast-fed was found to be associated with a 21% reduction in risk of childhood acute leukemias (odds ratio [OR] for all types combined = 0.79; 95% confidence interval [CI] = 0.70-0.91). A reduction in risk was seen separately for AML (OR = 0.77; 95% CI = 0.57-1.03) and ALL (OR = 0.80; 95% CI = 0.69-0.93). The inverse associations were stronger with longer duration of breast-feeding for total ALL and AML; for M0, M1, and M2 morphologic subtypes of AML; and for early pre-B-cell ALL., Conclusion: In this study, breast-feeding was associated with a reduced risk of childhood acute leukemia. If confirmed in additional epidemiologic studies, our findings suggest that future epidemiologic and experimental efforts should be directed at investigating the anti-infective and/or immune-stimulatory or immune-modulating effects of breast-feeding on leukemogenesis in children.

The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.

Background: Colorectal cancer is the third most common cancer in the world, arising mostly from pre-existing adenomatous polyps (adenomas) of the large bowel. Patients with colorectal adenomas are at increased risk of colorectal cancer because of a high recurrence rate for adenomas. We followed a cohort of 1490 patients with rectal adenomas to determine whether recurrence might be related to pathologic characteristics of the initial adenomas., Methods: The patients were identified in Haining County, China, from 1977 through 1978 by means of examination with a 15-cm rigid sigmoidoscope. They were followed by endoscopic examination at years 2, 4, 6, 11, and 16 after their initial polypectomy. New adenomas in the rectum were identified in 280 patients in these follow-up examinations., Results: Statistically significant twofold to threefold elevated risks of metachronous (recurrent) adenomas were observed for patients who had more than two initial adenomas or whose most advanced initial adenoma was more than 1.0 cm in size, was of villous/tubulovillous type, or showed moderate to severe dysplasia. Much stronger associations were observed for advanced metachronous neoplasms, which are defined as cancers or adenomas with severe dysplasia, with multivariate adjusted relative risks (95% confidence interval) of 4.2 (1.8-9.9) for a large initial adenoma (>1.0 cm), 8.1 (4.2-15.6) for villous/tubulovillous architecture, and 14.4 (5.0-41.3) for severe dysplasia. In particular, patients who had a large (>1.0 cm) adenoma with severe dysplasia at baseline had a relative risk of 37 (7.8-174.7) of developing advanced metachronous neoplasms compared with patients who had small adenoma(s) with mild dysplasia., Conclusions: The risk of metachronous adenomas is closely related to the pathology of initial adenomas, thus allowing identification of a high-risk group of adenoma patients for close surveillance after their initial polypectomy.

Background: It has been suggested that certain medical conditions and drug exposures might suppress the immune system and increase the risk of developing non-Hodgkin's lymphoma (NHL)., Purpose: We investigated whether specific medical conditions and drug exposures were associated with the risk of NHL in a cohort of older women who were enrolled in the Iowa Women's Health Study., Methods: A cohort of 41837 women, 55-69 years of age at baseline, was followed prospectively for the development of cancer from 1986 through 1992. These women had completed a baseline questionnaire in January 1986 that inquired about the occurrence and age at onset of specific medical conditions, about family history of cancer, and about the use of selected medications. Follow-up questionnaires were mailed to the women in 1987, 1989, and 1992. Incident cancers and deaths were ascertained through linkages to state and national databases. For most analyses, women with a self-reported history of cancer at baseline (n = 3903) were excluded. Relative risks (RRs) and 95% confidence intervals (CIs), adjusted for age or for age and other variables, were used as a measure of the association between NHL and medical history factors. Reported P values are two-sided., Results: One hundred fourteen incident cases of NHL were identified in the cohort during follow-up. A history of adult-onset diabetes mellitus (i.e., first diagnosed after the age of 30 years) was associated with an increased risk of developing NHL (age-adjusted RR = 2.18; 95% CI = 1.22-3.90). In addition, there was an association between the duration of adult-onset diabetes and increasing risk of NHL (P for trend = .004), with an age-adjusted RR of 2.90 (95% CI = 1.07-7.90) for women with a diagnosis of diabetes for 15 or more years compared with women with no diagnosis of diabetes. Women with a history of blood transfusion were also at increased risk for the development of NHL (age-adjusted RR = 1.95; 95% CI = 1.33-2.85). The risk estimates for diabetes and transfusion history were independent of each other and were not changed substantially after adjustment for other risk factors. History of a previous cancer (excluding hematopoietic and lymphatic cancers) was associated with an increased risk of NHL (age-adjusted RR = 1.92; 95% CI = 1.21-3.06); this risk estimate was attenuated somewhat after adjustment for a history of diabetes, transfusion history, and other major risk factors (RR = 1.66; 95% CI = 1.02-2.69). No statistically significant associations were found between NHL and a history of chronic colitis, nonestrogen steroid use, use of exogenous estrogens, or use of thyroid medications., Conclusions and Implications: A history of adult-onset diabetes mellitus, blood transfusion, and a history of cancer (or its treatment) appear to be independent risk factors for NHL in older women.

In the past decade, significant progress has been made in understanding the genetic component of familial cancers. Genes associated with familial colon and breast cancers have recently been isolated and molecular diagnostic tests are expected to become available in the near future. Clinicians now have the opportunity to recognize and counsel individuals with elevated risk of cancer by identifying risk factors and genes associated with cancer predisposition. The rapid advances in molecular technology are a direct challenge to the medical community and cancer centers to supply specialized clinical services for familial cancers. We sought to ascertain the activities of cancer centers in the development of programs and the provision of genetic services for familial cancer. We surveyed 41 centers with National Cancer Institute (NCI) cancer center support grants. One half of the centers responding (17 of 34) reported that they provide some genetic services for familial cancer. About one half of these 17 centers (eight [57%] of 14; the three remaining clinics that responded had incomplete information on this indicator) see a variety of patient types on a small scale (fewer than 100 patients per year), and most provide four basic clinical evaluations: medical evaluation, cancer risk assessment, genetic counseling, and pedigree analysis. Staffing of each center varied widely, as did the types of screening services offered (including molecular diagnostic testing). Several centers (six [35%] of 17) indicated that they were in the developmental stages for serving familial cancer patients, and many seem to be increasing their activities in this area. The remaining 17 NCI-supported centers that responded, however, currently provide no genetic services for familial cancers. The results of this survey suggest that there is interest in developing clinical programs for familial cancers by NCI-supported cancer centers, but most of these programs are in developmental stages. A base line has been established to monitor future progress for the provision of cancer genetic services.

Background: The kinetics of colorectal epithelial cell proliferation is altered in patients at increased risk for colon cancer. Calcium administration ameliorates such proliferative changes in rodents. Findings in preliminary clinical trials have suggested similar effects in humans., Purpose: A randomized, double-blind, placebo-controlled, clinical trial was designed to determine whether calcium supplementation will reduce the colorectal epithelial cell proliferation rate and normalize the distribution of proliferating cells within colorectal crypts (i.e., shift the zone of proliferation from the entire crypt to the lower 60% of the crypt, which is thought to be the normal proliferative zone of the crypt) in patients with sporadic adenomas., Methods: Sporadic adenoma patients (n = 193) were treated with placebo (n = 66), 1.0 g calcium (n = 64), or 2.0 g calcium (n = 63) daily for 6 months. Rectal mucosa biopsy specimens were obtained at base line and at 1-, 2-, and 6-month follow-up. Cell proliferation was measured by detection of S-phase-associated proliferating cell nuclear antigen by immunohistochemical methods. The cell proliferation rate, called labeling index (LI), was calculated as the proportion of labeled cells in the crypts. The deviation of the proliferative zone from the normal location in the lower 60% of the crypt was calculated as the proportion of labeled cells in the upper 40% of the crypt, called distributional index (phi h). The effects of calcium treatment on the LI and phi h were expressed as relative effects--(calcium follow-up/calcium base line)/(placebo follow-up/placebo base line). Calculations and inference testing of the relative effects were accomplished using a repeated-measures mixed model on log-transformed LI and phi h values. All statistical tests were two-sided., Results: Scorable biopsy specimens were obtained on 170 patients at base line, 164 at 1 month, 161 at 2 months, and 163 at 6 months. The difference in the change in the LI between the combined calcium groups and the placebo group was insignificant, with a relative effect of calcium versus placebo of 0.97 (P = .87). However, for the phi h, the relative effect of calcium versus placebo was 0.50 (P = .05) in the combined calcium groups, 0.56 (P = .16) in the 1.0-g calcium group, and 0.44 (P = .05) in the 2.0-g calcium group., Conclusions: Calcium supplementation normalizes the distribution of proliferating cells without affecting the proliferation rate in the colorectal mucosa of sporadic adenoma patients., Implications: These results support further study of whether alterations in colon cell proliferative kinetics represent true intermediate steps in colon carcinogenesis that can be used to investigate the etiology and prevention of, and whether a higher calcium consumption can reduce the risk of, colon cancer.

Background: Previous studies have suggested that cancers of the breast and prostate cluster in families and that the presence of both diseases in a family may be associated with increased risk of breast cancer., Purpose: Our purpose was to evaluate whether 1) prostate cancer aggregates in families with postmenopausal breast cancer, 2) families with cancers of the breast and prostate are the same ones as families with cancers of the breast and ovary, and 3) a family history of prostate cancer is associated with increased risk of postmenopausal breast cancer., Methods: We analyzed data from a large prospective cohort study of Iowa women that were (at baseline) aged 55-69 years in 1986. At the third follow-up survey in 1992, self-reported data on family history of breast, ovarian, and prostate cancers in parents and siblings were provided by 30,883 women. Additional information was collected to ascertain whether the age-of-onset of breast cancer in mothers or sisters was before or after the age of 45 years. Cancer occurrence was documented using the State Health Registry of Iowa., Results: History of prostate cancer in their father or a brother was reported by 3384 (11.0%) of the women, and a total of 4090 women (13.2%) reported breast cancer in their mother or a sister. A positive family history of both cancers was reported by 556 women, significantly (two-sided P < .001) greater than the 457 women expected if the family histories were independent. The aggregation of breast, prostate, and ovarian cancers was reported by 22 participants, greater than the 2.7 expected (two-sided P < .0001). During 6 years of follow-up, 578 breast cancers were identified in the cohort at risk. Compared with women without a family history of either cancer, women with a family history of breast cancer had a relative risk (RR) of 1.37 (95% confidence interval [CI] = 1.06-1.79) if the affected relative had onset after the age of 45 years, and an RR of 1.71 (95% CI = 1.13-2.61) if the affected relative had onset at or before the age of 45. A family history of prostate cancer in the absence of a family history of breast cancer was associated with an RR of 1.19 (95% CI = .90-1.56). However, a family history of both breast and prostate cancers was associated with RRs of 2.06 (95% CI = 1.23-3.45) and 2.35 (95% CI = .97-5.67) for breast cancer onset in relatives of greater than 45 and less than or equal to 45 years, respectively., Conclusions: These observations are concordant with recent reports that suggest a shared familial risk (inherited or environmental) for these hormone-dependent malignancies.

Background: Colonic epithelial cell proliferation is increased in patients at high risk for colon cancer. Calcium administration has ameliorated the proliferative changes in rodents, and findings in small, uncontrolled clinical trials have suggested similar effects in humans., Purpose: This preliminary, double-blind, randomized clinical trial was designed 1) to investigate whether supplemental calcium will reduce colonic epithelial cell proliferation in patients with sporadic adenomas who consume a high-fat, Western-style diet; 2) to determine the sample size (number of scorable crypts per person) needed to achieve adequate statistical power; and 3) to evaluate the feasibility of full-scale clinical trials., Methods: Twenty-one sporadic adenoma patients were treated daily with placebo or 1200 mg of supplemental calcium. To determine colonic epithelial cell proliferation, we used tritiated thymidine labeling of colon crypt epithelial cells in rectal biopsy specimens and calculated the percentage of labeled cells (labeling index [LI]). Two pathology technician "readers" independently scored each specimen, and inter-reader reliability was determined. Subjects remained on their usual diet during the study, and intake of calories, calcium, total fat, and vitamin D did not differ substantially among them. We calculated curves for statistical power to determine the number of scorable crypts needed per person for detection of a statistically significant difference (P < .05) of 1.0% in mean LI., Results: The pooled baseline LI was 4.7%. In the calcium-treated group, the LI increased 0.6% (proportional increase, 12.8%); in the placebo-treated group, it decreased 0.5% (proportional decrease, 10.6%). The difference between change in the mean LI from baseline to 8 weeks' follow-up in the placebo group versus the calcium group was not statistically significant. The intraclass correlation coefficient for inter-reader reliability for the baseline LI was .66. Analyses indicated scoring eight crypts sufficient for estimates of the LI adequate for between-group comparisons, a level achieved in 81% of biopsy specimens., Conclusions: Calcium carbonate supplements delivering 1200 mg elemental calcium daily may not decrease colonic epithelial cell proliferation over an 8-week period in sporadic adenoma patients. In future trials measuring the LI, consideration should be given to ensuring adequate numbers of scorable crypts and to the impact of inadequate biopsy procedures, labeling failure, reader reliability, and participant withdrawal. Our findings support the feasibility of a full-scale clinical trial to further study the relationships among dietary calcium, colonic epithelial cell proliferation, and colorectal cancer.

Background: Although the results of animal studies and cross-cultural comparisons generally support a role for dietary fat in the etiology of breast cancer, results of analytic epidemiology studies are equivocal., Purpose: The association between dietary fat and subsequent breast cancer was examined in a cohort of 34,388 postmenopausal women from Iowa., Methods: Dietary habits were assessed by a food-frequency questionnaire mailed in January 1986. Through December 31, 1989, 459 incident cases of breast cancer occurred in this cohort. Proportional hazards regression was used to examine the dietary fat-breast cancer association while adjusting for potential confounders. The effects on this association of four analytic approaches to adjustment for energy intake were also considered., Results: After adjustment for known determinants of breast cancer, a modest positive association of total fat intake with risk of breast cancer was seen. Polyunsaturated fat intake was also positively associated with breast cancer (relative risk from lowest to highest intake, 1.0, 1.25, 1.31, and 1.49; P for trend = .052). Different approaches to adjustment for energy intake, however, provided different impressions of the dietary fat-breast cancer association. One method, involving categorization of crude fat intake and inclusion of total energy intake in regression analysis, gave relative risk estimates from low to high fat intake of 1.0, 1.17, 1.25, and 1.38 (P for trend = .18). Another method, based on categorization of fat intake residuals in which the variation in fat due to total energy intake was removed, gave corresponding estimates of 1.0, 1.24, 1.30, and 1.16 (P for trend = .29). The former suggests increasing breast cancer risk with increasing fat intake; the latter suggests no association., Conclusions: These results are consistent with other cohort studies that have shown a weak association or no association between dietary fat and breast cancer. They are also consistent with studies suggesting that fat intake is a determinant of breast cancer, particularly after accounting for inaccuracies in dietary assessment. The effects of different energy-adjustment methods may account in part for the varying interpretations of four previous cohort studies of dietary fat and breast cancer., Implications: Further work is needed to clarify not only the nature of the dietary fat-breast cancer association, but also the impact of different analytic methods used in the investigation of diet-disease associations.

A community-based case-control study of the effect of reproductive factors on risk of large bowel cancer in Australia is described. The study involved 155 cases (99 colon cancer, 56 rectal cancer) and 311 controls who were interviewed with regard to pregnancies and their outcomes, lactation, menstrual history, and oral contraceptive (OC) use. Increasing parity was associated with a decreasing risk of colon cancer; para 0, relative risk (RR)=1; para 1-2, RR=0.9, 95% confidence interval (CI)=0.4-1.8; para greater than or equal to 3, RR=0.4, 95% CI=0.2-0.8; later age at first live birth (AFLB) was associated with increasing risk (AFLB less than or equal to 21 yr, RR=1; 22-25 yr, RR=2.3, 95% CI=1.0-5.5; greater than or equal to 26 yr, RR=2.7, 95% CI=1.2-6.2). These effects were independent of each other. Parity appeared to exert its predominant effect on risk of cancer of the right colon. OC use was more common among controls than cases (RR=0.5; 95% CI=0.3-1.2 for ever vs. never users) and showed a dose-response effect in multiple logistic analysis. The pattern of point-estimate RR for rectal cancer was largely congruent with those for colon cancer but was not significantly different from 1.0.

In 1979-81, 419 patients with incident cases of colon and rectal cancer and 732 controls were questioned regarding diet and alcohol. Cancer cases were a population-based series reported to the South Australian Central Cancer Registry, were 30-74 years of age, and were residing in Metropolitan Adelaide. Controls were selected from the electoral roll and individually age- and sex-matched to cancer cases. The most consistent risk factor for colorectal cancer was dietary protein, which was associated with a twofold-to-threefold relative risk for colon cancer and for rectal cancer in women for all levels of consumption above the base line (i.e., the lowest consumption quintile). For male colon cancer the corresponding relative risk was similar; but for male rectal cancer, risk was elevated only at old ages. Total energy intake and, less clearly, meal frequency were also positively associated with increased risk. Total alcohol intake (but not specifically beer) was associated with increased risk of both colon and rectal cancer in women; in both sexes, there was an increased risk of colon and rectal cancer associated with spirits consumption. A reduced risk of rectal cancer was associated with vitamin C but not with vitamin A. The increased risk associated with high protein and total energy was confined to those consuming a low fiber diet, particularly among women; but some other aspects of the relationship between fiber consumption and risk of colorectal cancer were more complex. Some modifications and extensions of the current fat-to-bile acid-to-fiber theory of bowel carcinogenesis were suggested.