Study Of Colorectal Cancer Risk Research Articles

Association of CDH1 Germline Variants and Colon Polyp Phenotypes in Patients with Hereditary Diffuse Gastric Cancer.

Germline CDH1 variants resulting in E-cadherin loss of function result in an increased risk of diffuse type gastric cancer and lobular type breast cancer. However, the risk of developing other epithelial neoplasms, specifically colorectal cancer, is unknown. Patients enrolled in a prospective natural history study of hereditary gastric cancer who underwent at least one colonoscopy were evaluated. Out of 300 patients with CDH1 pathogenic or likely pathogenic variants, 85 underwent colonoscopy. More than half of patients (56%, 48/85) had at least one colorectal polyp. Most of those patients (83%, 40/48) had at least one precancerous polyp (adenoma or sessile serrated lesion). More than half (56%) of patients younger than age 45 had a colorectal polyp. Of those with polyps, the most frequent CDH1 variant type was canonical splice site (27%, 13/48) followed by nonsense (21%, 10/48). There was no association between CDH1 variant type and increased likelihood of colorectal polyps. In summary, a majority of CDH1 variant carriers who underwent colonoscopy had colorectal polyps detected, and most subjects were less than 45 years old. This study of colorectal cancer risk based on the prevalence of colorectal polyps in the CDH1 population requires further investigation to appropriately counsel patients on colorectal cancer screening. Clinical trial registry website: https://clinicaltrials.gov/. Clinical trial number: NCT03030404.

Sa1026 – Developing a Study of Colorectal Cancer Risk and Protective Factors Among Alaska Native People Using a Community-Based Participatory Research Framework

Sa1026 – Developing a Study of Colorectal Cancer Risk and Protective Factors Among Alaska Native People Using a Community-Based Participatory Research Framework

Abstract 4841: GSTM1 and GSTT1 polymorphisms in population-based study of colorectal cancer risk.

Abstract Introduction: Colorectal cancer (CRC) remains a significant cause of mortality accounting for 10% of all deaths of malignancies in European Caucasians. Glutathione S-transferases (GSTs) participate in the detoxification of chemotherapeutic agents used in therapy of CRC. Genetic polymorphisms in GST genes (copy-number variants of GSTM1 and GSTT1) that lead to diminished enzyme activity have been associated with CRC risk and survival increased chemotherapeutic treatment benefit in patients in most of the studies. Aims: In this study we examined associations of GSTM1 and GSTT1 genotypes and clinical factors (age, gender, stage, localization of the tumor) with risk and we assessed the effect of genetic polymorphisms in GST genes on survival in CRC patients treated with adjuvant/palliative chemotherapy. Materials & methods: We followed 1106 CRC patients treated with chemotherapy based on fluoropyrimidines and 1343 unrelated controls. Polymorphisms were genotyped by a relative quantification method (copy-number variants of GSTM1 and GSTT1), and PCR followed by gel electrophoresis (null/non-null genotypes for GSTM1 and GSTT1). Statistical evaluations of risk were evaluated using the Pearson Chi-Square Test. Associations between genotypes and overall survival were assessed using Kaplan-Meier curves and Cox proportional hazards regression. Results: GSTT1 null was associated with a small but significant increase in risk (p = 0.013, OR = 1.393, 95% CI = 1.007-1.818). Copy-number variants of GSTM1 was associated with a reduction of risk (pDominant model < 0.001, OR = 0.673, 95% CI = 0.552-0.820). The same associations were founded in male cases after gender stratification. There were no significant associations between GSTT1 and GSTM1 genotypes with other clinical factors (localization, stage and tumor node metastasis classification) in the total case group. However, following stratification by age (<70 vs ≥70 years at diagnosis), in young patients, GSTT1 null was associated with an increased risk (p < 0.001, OR = 1.942, 95% CI = 1.523-3.440). Furthermore, GSTM1 null and GSTT1 copy number variation were associated with low survival rates in younger patients (p = 0.047, HR = 3.937; p = 0.039, HR = 4.246). However, survival increase is observed in young patients with GSTM1 copy number variant (pDominant model < 0.001, HR = 13.246). Conclusions: This study confirms the association with the risk and the effect of GSTT1 and GSTM1 polymorphisms on survival in CRC patients who received chemotherapy. We also suggest a specific risk association with GST null genotype in younger patients, particularly in those with presentation of tumor under the age of 70 years. The null GST genotype could be related to an improved immune response in younger patients, but less detoxification and increased rates of DNA damage in older patients. Citation Format: Silvia Boffo, Erika Cecchin, Flavio Rizzolio, Sara Lonardi, Vittorina Zagonel, Pasquale Fiduccia, Giuseppe Toffoli. GSTM1 and GSTT1 polymorphisms in population-based study of colorectal cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4841. doi:10.1158/1538-7445.AM2013-4841

Chromosome 8q23.3, 10p14 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome – a combined analysis of the Australian, Dutch and Polish Lynch syndrome cohorts

Background For a decade researchers have been searching for modifier genes in individuals with a molecular diagnosis of Lynch syndrome but the task has proven difficult as discordant results seem to be the rule rather than the exception. Recently, two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome patients irrespective of which gene was mutated. In a combined study of CRC risk in Australian and Polish Lynch syndrome patients only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three datasets was performed to better define this association.

A longitudinal study of serum insulin and glucose levels in relation to colorectal cancer risk among postmenopausal women

Background:It is unclear whether circulating insulin or glucose levels are associated with increased risk of colorectal cancer. Few prospective studies have examined this question, and only one study had repeated measurements.Methods:We conducted a prospective study of colorectal cancer risk using the subsample of women in the Women's Health Initiative study whose fasting blood samples, collected at baseline and during follow-up, were analysed for insulin and glucose. Cox proportional hazards models were used to assess associations with colorectal cancer risk in both baseline and time-dependent covariates analyses.Results:Among 4902 non-diabetic women with baseline fasting serum insulin and glucose values, 81 incident cases of colorectal cancer were identified over 12 years of follow-up. Baseline glucose levels were positively associated with colorectal cancer and colon cancer risk: multivariable-adjusted hazard ratio (HR) comparing the highest (⩾99.5 mg dl−1) with the lowest tertile (<89.5 mg dl−1): 1.74, 95% confidence interval (CI) 0.97–3.15 and 2.25, 95% CI: 1.12–4.51, respectively. Serum insulin and homeostasis model assessment were not associated with risk. Analyses of repeated measurements supported the baseline results.Conclusion:These data suggest that elevated serum glucose levels may be a risk factor for colorectal cancer in postmenopausal women.

Association of Metabolic Syndrome With Proximal and Synchronous Colorectal Neoplasm

Metabolic syndrome and its associated morbidities have become a major public health problem in both developed and developing countries. Insulin resistance, the core mechanism of metabolic syndrome, has been associated with the development of colorectal neoplasm, but the interrelation between metabolic syndrome and colon cancer is rarely addressed. Our study aimed to determine whether metabolic syndrome is associated with the risk and clinical presentation of colorectal neoplasia. Consecutive 4277 ethnic Chinese who received complete total colonoscopy and thorough health checkups were enrolled. Both National Cholesterol Education Program's Adult Treatment Panel III and modified Asian criteria were used for defining metabolic syndrome. Logistic regression modeling was used to elucidate the association between colorectal neoplasia and metabolic syndrome. The impact of metabolic syndrome on distribution and number of colorectal neoplasia was also assessed. Of all those enrolled, 27.1% of men and 18.9% of women met the criteria of metabolic syndrome, and 9.8% had colorectal neoplasia. Metabolic syndrome was associated with odds ratio (OR) of 1.35 (95% confidence interval [CI], 1.05-1.73) for colorectal neoplasia. OR was 0.96 (95% CI, 0.67-1.38) for distal lesions, 1.62 (95% CI, 1.14-2.30) for proximal lesions, 2.15 (95% CI, 1.40-3.31) for synchronous lesions, and 2.30 (95% CI, 1.42-3.72) for synchronous lesions located at both sides of colon. Subjects with metabolic syndrome have a higher risk of colon neoplasia at the proximal colon and synchronous lesions at both sides of the colon. These findings will help future colon cancer screening and prevention in patients with metabolic syndrome.

Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis.

A sedentary lifestyle, obesity, and a Westernized diet have been implicated in the aetiology of both colorectal cancer and non-insulin dependent diabetes mellitus, leading to the hypothesis that hyperinsulinaemia may promote colorectal cancer. We prospectively examined the association between colorectal cancer risk and factors related to insulin resistance and hyperinsulinaemia, including BMI, physical activity, diabetes mellitus, and blood glucose, in a cohort of 75 219 Norwegian men and women. Information on incident cases of colorectal cancer was made available from the Norwegian Cancer Registry. Reported P values are two-sided. During 12 years of follow up, 730 cases of colorectal cancer were registered. In men, but not in women, we found a negative association with leisure-time physical activity (P for trend = 0.002), with an age-adjusted RR for the highest versus the lowest category of activity of 0.54 (95% CI = 0.37–0.79). Women, but not men, with a history of diabetes were at increased risk of colorectal cancer (age-adjusted RR = 1.55; 95% CI = 1.04–2.31), as were women with non-fasting blood glucose ≥8.0 mmol l−1(age-adjusted RR = 1.98; 95% CI = 1.31–2.98) compared with glucose <8.0 mmol l−1. Overall, we found no association between BMI and risk of colorectal cancer. Additional adjustment including each of the main variables, marital status, and educational attainment did not materially change the results. We conclude that the inverse association between leisure-time physical activity and colorectal cancer in men, and the positive association between diabetes, blood glucose, and colorectal cancer in women, at least in part, support the hypothesis that insulin may act as a tumour promoter in colorectal carcinogenesis. © 2001 Cancer Research Campaign http://www.bjcancer.com

More About: Prospective Study of Colorectal Cancer Risk in Men and Plasma Levels of Insulin-Like Growth Factor (IGF)-I and IGF-Binding Protein-3

Background: Insulin-like growth factor-I (IGF-I) is a potent mitogen for normal and neoplastic cells, whereas IGF-binding protein-3 (IGFBP-3) inhibits cell growth in many experimental systems. Acromegalics, who have abnormally high levels of growth hormone and IGF-I, have higher rates of colorectal cancer. We therefore examined associations of plasma levels of IGF-I and IGFBP-3 with the risk of colorectal cancer in a prospective case-control study nested in the Physicians' Health Study. Methods: Plasma samples were collected at baseline from 14916 men without diagnosed cancer. IGF-I, IGF-II, and IGFBP-3 were assayed among 193 men later diagnosed with colorectal cancer during 14 years of follow-up and among 318 age- and smoking-matched control subjects. All P values are two-sided. Results: IGFBP-3 levels correlated with IGF-I levels (r = .64) and with IGF-II levels (r = .90). After controlling for IGFBP-3, age, smoking, body mass index (weight in kg/[height in m] 2 ), and alcohol intake, men in the highest quintile for IGF-I had an increased risk of colorectal cancer compared with men in the lowest quintile (relative risk [RR] = 2.51; 95% confidence interval [CI] = 1.15-5.46; P for trend = .02). After controlling for IGF-I and other covariates, men with higher IGFBP-3 had a lower risk (RR = 0.28; 95% CI = 0.12-0.66 ; P for trend = .005, comparing extreme quintiles). The associations were consistent during the first and the second 7-year follow-up intervals and among younger and older men. IGF-II was not associated with risk. Conclusions: Our findings suggest that circulating IGF-I and IGFBP-3 are related to future risk of colorectal cancer.

RESPONSE: more about: prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3

RESPONSE: more about: prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3

RESPONSE: More About: Prospective Study of Colorectal Cancer Risk in Men and Plasma Levels of Insulin-Like Growth Factor (IGF)-I and IGF- Binding Protein-3

RESPONSE: More About: Prospective Study of Colorectal Cancer Risk in Men and Plasma Levels of Insulin-Like Growth Factor (IGF)-I and IGF- Binding Protein-3

RESPONSE: Re: Prospective Study of Colorectal Cancer Risk in Men and Plasma Levels of Insulin-Like Growth Factor (IGF)-I and IGF-Binding Protein-3.

RESPONSE: Re: Prospective Study of Colorectal Cancer Risk in Men and Plasma Levels of Insulin-Like Growth Factor (IGF)-I and IGF-Binding Protein-3.

Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3.

Insulin-like growth factor-I (IGF-I) is a potent mitogen for normal and neoplastic cells, whereas IGF-binding protein-3 (IGFBP-3) inhibits cell growth in many experimental systems. Acromegalics, who have abnormally high levels of growth hormone and IGF-I, have higher rates of colorectal cancer. We therefore examined associations of plasma levels of IGF-I and IGFBP-3 with the risk of colorectal cancer in a prospective case-control study nested in the Physicians' Health Study. Plasma samples were collected at baseline from 14916 men without diagnosed cancer. IGF-I, IGF-II, and IGFBP-3 were assayed among 193 men later diagnosed with colorectal cancer during 14 years of follow-up and among 318 age- and smoking-matched control subjects. All P values are two-sided. IGFBP-3 levels correlated with IGF-I levels (r=.64) and with IGF-II levels (r=.90). After controlling for IGFBP-3, age, smoking, body mass index (weight in kg/[height in m]2), and alcohol intake, men in the highest quintile for IGF-I had an increased risk of colorectal cancer compared with men in the lowest quintile (relative risk [RR]=2.51; 95% confidence interval [CI]=1.15-5.46; P for trend = .02). After controlling for IGF-I and other covariates, men with higher IGFBP-3 had a lower risk (RR=0.28; 95% CI=0.12-0.66; P for trend = .005, comparing extreme quintiles). The associations were consistent during the first and the second 7-year follow-up intervals and among younger and older men. IGF-II was not associated with risk. Our findings suggest that circulating IGF-I and IGFBP-3 are related to future risk of colorectal cancer.

Long-term therapy with sulphasalazine protects against colorectal cancer in ulcerative colitis: a retrospective study of colorectal cancer risk and compliance with treatment in Leicestershire.

The aims of this study were to (i) estimate the prognosis of a 10-year cohort as expressed by risk of colectomy and risk of development of colorectal cancer, and (ii) assess the impact of long-term sulphasalazine on the natural course of ulcerative colitis. One hundred and seventy-five patients diagnosed between 1972 and 1981 with either total colitis (n = 143) or with limited ulcerative colitis but deceased (n = 32) were identified. Overall there was 98% case ascertainment and verification. A total of 49 patients underwent a colectomy, 6 as emergency laparotomies, 36 for failed medical management and 7 for known colorectal cancer, giving a crude colectomy rate of 23.2%. The colectomy rate was 7.2% in the year of diagnosis, decreasing in frequency over the next 4 years, then reaching a steady state of approximately 1.7% per year. In the total cohort, colorectal cancer occurred in 10 patients within the study period. The cumulative incidence of colorectal cancer 10 years after diagnosis was 2.1% and at 20 years 7.4% for the total group of patients excluding those with a colectomy. The mean duration of ulcerative colitis before diagnosis was 7.9 years (range 5-12). The crude proportions developing cancer were 5/152 (3%) in the group who took long-term sulphasalazine but 5/16 (31%) in the those who had had their treatment stopped or who did not comply with therapy. This is highly significant using a simple chi 2 test (chi 2 = 20.2, df = 1, P < 0.001). Two methods were used for survival analyses, the log-rank and the generalized Wilcoxon methods. Both give highly significant values for the crude effect of compliance (P < 0.001). Patients with ulcerative colitis who were not on long-term sulphasalazine or 5-aminosalicylic acid therapy (either because a doctor stopped it or they did not comply with treatment) were significantly more likely to develop colorectal cancer than their compliant counterparts.