Michael Hoffmeister

Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21.

In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 × 10−10), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 × 10−26) and 18q21 (rs4939827; OR = 1.2; P = 7.8 × 10−28). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75–3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.

Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 × 10−10), 16q22.1 (rs9929218, CDH1; P = 1.2 × 10−8), 19q13.1 (rs10411210, RHPN2; P = 4.6 × 10−9) and 20p12.3 (rs961253; P = 2.0 × 10−10). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.

Protection From Colorectal Cancer After Colonoscopy: A Population-Based, Case–Control Study

BACKGROUND Colonoscopy with detection and removal of adenomas is considered a powerful tool to reduce colorectal cancer (CRC) incidence. However, the degree of protection achievable in a population setting with high-quality colonoscopy resources remains to be quantified. OBJECTIVE To assess the association between previous colonoscopy and risk for CRC. DESIGN Population-based case-control study. SETTING Rhine-Neckar region of Germany. PATIENTS A total of 1688 case patients with colorectal cancer and 1932 control participants aged 50 years or older. MEASUREMENTS A detailed lifetime history of CRC risk factors and preventive factors, including history and results of previous colonoscopies, and of medical data obtained by self-reports and medical records. Odds ratios of CRC associated with colonoscopy in the preceding 10 years were estimated, after adjustment for sex, age, education level, participation in a general health screening examination, family history of CRC, smoking status, body mass index, and use of nonsteroidal anti-inflammatory drugs or hormone replacement therapy. RESULTS Overall, colonoscopy in the preceding 10 years was associated with 77% lower risk for CRC. Adjusted odds ratios for any CRC, right-sided CRC, and left-sided CRC were 0.23 (95% CI, 0.19 to 0.27), 0.44 (CI, 0.35 to 0.55), and 0.16 (CI, 0.12 to 0.20), respectively. Strong risk reduction was observed for all cancer stages and all ages, except for right-sided cancer in persons aged 50 to 59 years. Risk reduction increased over the years in both the right and the left colon. LIMITATION The study was observational, with potential for residual confounding and selection bias. CONCLUSION Colonoscopy with polypectomy can be associated with strongly reduced risk for CRC in the population setting. Aside from strong risk reduction with respect to left-sided CRC, risk reduction of more than 50% was also seen for right-sided colon cancer. PRIMARY FUNDING SOURCE German Research Council and German Federal Ministry of Education and Research.

Protection From Right- and Left-Sided Colorectal Neoplasms After Colonoscopy: Population-Based Study

BACKGROUND Colonoscopy is used for early detection and prevention of colorectal cancer, but evidence on the magnitude of overall protection and protection according to anatomical site through colonoscopy performed in the community setting is sparse. We assessed whether receiving a colonoscopy in the preceding 10-year period, compared with no colonoscopy, was associated with prevalence of advanced colorectal neoplasms (defined as cancers or advanced adenomas) at various anatomical sites. METHODS A statewide cross-sectional study was conducted among 3287 participants in screening colonoscopy between May 1, 2005, and December 31, 2007, from the state of Saarland in Germany who were aged 55 years or older. Prevalence of advanced colorectal neoplasms was ascertained by screening colonoscopy and histopathologic examination of any polyps excised. Previous colonoscopy history was obtained by standardized questionnaire, and its association with prevalence of advanced colorectal neoplasms was estimated, after adjustment for potential confounding factors by log-binomial regression. RESULTS Advanced colorectal neoplasms were detected in 308 (11.4%) of the 2701 participants with no previous colonoscopy compared with 36 (6.1%) of the 586 participants who had undergone colonoscopy within the preceding 10 years. After adjustment, overall and site-specific adjusted prevalence ratios for previous colonoscopy in the previous 10-year period were as follows: overall, 0.52 (95% confidence interval [CI] = 0.37 to 0.73); cecum and ascending colon, 0.99 (95% CI = 0.50 to 1.97); hepatic flexure and transverse colon, 1.21 (95% CI = 0.60 to 2.42); right-sided colon combined (cecum to transverse colon), 1.05 (95% CI = 0.63 to 1.76); splenic flexure and descending colon, 0.36 (95% CI = 0.16 to 0.82); sigmoid colon, 0.29 (95% CI = 0.16 to 0.53); rectum, 0.07 (95% CI = 0.02 to 0.40); left colon and rectum combined (splenic flexure to rectum, referred to as left-sided elsewhere), 0.33 (95% CI = 0.21 to 0.53). CONCLUSION Prevalence of left-sided advanced colorectal neoplasms, but not right-sided advanced neoplasms, was strongly reduced within a 10-year period after colonoscopy, even in the community setting.

Effect of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and mortality: systematic review and meta-analysis of randomised controlled trials and observational studies

Objectives To review, summarise, and compare the evidence for effectiveness of screening sigmoidoscopy and screening colonoscopy in the prevention of colorectal cancer occurrence and deaths. Design Systematic review and meta-analysis of randomised controlled trials and observational studies. Data sources PubMed, Embase, and Web of Science. Two investigators independently extracted characteristics and results of identified studies and performed standardised quality ratings. Eligibility criteria Randomised controlled trials and observational studies in English on the impact of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and mortality in the general population at average risk. Results For screening sigmoidoscopy, four randomised controlled trials and 10 observational studies were identified that consistently found a major reduction in distal but not proximal colorectal cancer incidence and mortality. Summary estimates of reduction in distal colorectal cancer incidence and mortality were 31% (95% confidence intervals 26% to 37%) and 46% (33% to 57%) in intention to screen analysis, 42% (29% to 53%) and 61% (27% to 79%) in per protocol analysis of randomised controlled trials, and 64% (50% to 74%) and 66% (38% to 81%) in observational studies. For screening colonoscopy, evidence was restricted to six observational studies, the results of which suggest tentatively an even stronger reduction in distal colorectal cancer incidence and mortality, along with a significant reduction in mortality from cancer of the proximal colon. Indirect comparisons of results of observational studies on screening sigmoidoscopy and colonoscopy suggest a 40% to 60% lower risk of incident colorectal cancer and death from colorectal cancer after screening colonoscopy even though this incremental risk reduction was statistically significant for deaths from cancer of the proximal colon only. Conclusions Compelling and consistent evidence from randomised controlled trials and observational studies suggests that screening sigmoidoscopy and screening colonoscopy prevent most deaths from distal colorectal cancer. Observational studies suggest that colonoscopy compared with flexible sigmoidoscopy decreases mortality from cancer of the proximal colon. This added value should be examined in further research and weighed against the higher costs, discomfort, complication rates, capacities needed, and possible differences in compliance.

Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840 149 screening colonoscopies

Objectives: To derive age and sex specific estimates of transition rates from advanced adenomas to colorectal cancer by combining data of a nationwide screening colonoscopy registry and national data on colorectal cancer (CRC) incidence. Design: Registry based study. Setting: National screening colonoscopy programme in Germany. Patients: Participants of screening colonoscopy in 2003 and 2004 (n = 840 149). Main outcome measures: Advanced adenoma prevalence, colorectal cancer incidence, annual and 10 year cumulative risk of developing CRC among carriers of advanced adenomas according to sex and age (range 55–80+ years) Results: The age gradient is much stronger for CRC incidence than for advanced adenoma prevalence. As a result, projected annual transition rates from advanced adenomas to CRC strongly increase with age (from 2.6% in age group 55–59 years to 5.6% in age group ⩾80 years among women, and from 2.6% in age group 55–59 years to 5.1% in age group ⩾80 years among men). Projections of 10 year cumulative risk increase from 25.4% at age 55 years to 42.9% at age 80 years in women, and from 25.2% at age 55 years to 39.7% at age 80 years in men. Conclusions: Advanced adenoma transition rates are similar in both sexes, but there is a strong age gradient for both sexes. Our estimates of transition rates in older age groups are in line with previous estimates derived from small case series in the pre-colonoscopy era independent of age. However, our projections for younger age groups are considerably lower. These findings may have important implications for the design of CRC screening programmes.

Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis

BACKGROUND & AIMS Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)). CONCLUSIONS In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

Does a negative screening colonoscopy ever need to be repeated

Background and aims: Screening colonoscopy is thought to be a powerful and cost-effective tool to reduce colorectal cancer incidence and mortality. Whether and when colonoscopy with negative findings has to be repeated is not well defined. The aim of this study was to assess the long term risk of clinically manifest colorectal cancer among subjects with negative findings at colonoscopy. Patients: 380 cases and 485 controls participating in a population based case-control study in Germany. Methods: Detailed history and results of previous colonoscopies were obtained by interview and from medical records. Adjusted relative risks of colorectal cancer among subjects with a previous negative colonoscopy compared with those without previous colonoscopy were estimated according to time since colonoscopy. Results: Subjects with previous negative colonoscopy had a 74% lower risk of colorectal cancer than those without previous colonoscopy (adjusted odds ratio (aOR) = 0.26 (95% confidence interval, 0.16 to 0.40)). This low risk was seen even if the colonoscopy had been done up to 20 or more years previously. Particularly low risks were seen for sigma cancer (aOR = 0.13 (0.04 to 0.43)) and for rectal cancer (aOR = 0.19 (0.09 to 0.39)), and after a negative screening colonoscopy at ages 55 to 64 (aOR = 0.17 (0.08 to 0.39)) and older (aOR = 0.21 (0.10 to 0.41)). Conclusions: Subjects with negative findings at colonoscopy are at very low risk of colorectal cancer and might not need to undergo repeat colonoscopy for 20 years or more, if at all. The possibility of extending screening intervals to 20 years or more might reduce complications and increase the feasibility and cost-effectiveness of colonoscopy based screening programmes.

Gender differences in colorectal cancer: implications for age at initiation of screening

There is some variation regarding age at initiation of screening for colorectal cancer (CRC) between countries, but the same age of initiation is generally recommended for women and men within countries, despite important gender differences in the epidemiology of CRC. We have explored whether, and to what extent, these differences would be relevant regarding age at initiation of CRC screening. Using population-based cancer registry data from the US and national mortality statistics from different countries, we looked at cumulative 10-year incidence and mortality of CRC reached among men at ages 50, 55, and 60, and found that women mainly reached equivalent levels when 4 to 8 years older. The gender differences were remarkably constant across populations and over time. These patterns suggest that gender differentiation of age at initiation may be worthwhile to utilise CRC-screening resources more efficiently.

Reduced Risk of Colorectal Cancer Up to 10 Years After Screening, Surveillance, or Diagnostic Colonoscopy

BACKGROUND & AIMS Data from randomized controlled trials on the effects of screening colonoscopies on colorectal cancer (CRC) incidence and mortality are not available. Observational studies have suggested that colonoscopies strongly reduce the risk of CRC, but there is little specific evidence on the effects of screening colonoscopies. METHODS We performed a population-based case-control study of 3148 patients with a first diagnosis of CRC (cases) and 3274 subjects without CRC (controls) from the Rhine-Neckar region of Germany from 2003 to 2010. Detailed information on previous colonoscopy and potential confounding factors was collected by standardized personal interviews. Self-reported information on colonoscopies and their indications was validated by medical records. We used multiple logistic regression to assess the association between colonoscopy conducted for specific indications within the past 10 years and risk of CRC. RESULTS A history of colonoscopy was associated with a reduced subsequent risk of CRC, independently of the indication for the examination. However, somewhat stronger associations were found for examinations with screening indications (adjusted odds ratio [OR] 0.09, 95% confidence interval [CI] 0.07-0.13) than for examinations with diagnostic indications, such as positive fecal occult blood test result (OR, 0.33; 95% CI, 0.19-0.57), surveillance after a preceding colonoscopy (OR, 0.33; 95% CI, 0.24-0.45), rectal bleeding (OR, 0.28; 95% CI, 0.20-0.40), abdominal symptoms (OR, 0.15; 95% CI, 0.10-0.21), or other (OR, 0.21; 95% CI, 0.14-0.30). Colonoscopy was also associated with a reduced risk of cancer in the right colon, regardless of the indication, although to a smaller extent than for other areas of the colon (OR for screening colonoscopy, 0.22; 95% CI, 0.14-0.33). CONCLUSIONS In a population-based case-control study, the risk of CRC was strongly reduced up to 10 years after colonoscopy for any indication. Risk was particularly low after screening colonoscopy, even for cancer in the right colon.