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

Discovery of common and rare genetic risk variants for colorectal cancer.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.Goncalo R Abecasis has received compensation from 23andMe and Helix. He is currently an employee of Regeneron Pharmaceuticals. Heather Hampel performs collaborative research with Ambry Genetics, InVitae Genetics, and Myriad Genetic Laboratories, Inc., is on the scientific advisory board for InVitae Genetics and Genome Medical, and has stock in Genome Medical. Rachel Pearlman has participated in collaborative funded research with Myriad Genetics Laboratories and Invitae Genetics but has no financial competitive interest

Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses

Abstract: Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10−8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. Results: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04–1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76–0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02–1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96–1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2). Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour

Age-specific sequence of colorectal cancer screening options in Germany: A model-based critical evaluation.

BackgroundThe current organized screening program for colorectal cancer in Germany offers both sexes 5 annual fecal immunochemical tests (FITs) between ages 50 and 54 years, followed by a first screening colonoscopy at age 55 years if all of these FITs were negative. We sought to assess the implications of this approach for key parameters of diagnostic performance.Methods and findingsUsing a multistate Markov model, we estimated the expected detection rates of advanced neoplasms (advanced adenomas and cancers) and number needed to scope (NNS) to detect 1 advanced neoplasm at a first screening colonoscopy conducted at age 55 after 5 preceding negative FITs and compared them with the corresponding estimates for a first screening colonoscopy at age 55 with no preceding FIT testing. In individuals with 5 consecutive negative FITs undergoing screening colonoscopy at age 55, expected colonoscopy detection rate (NNS) was 3.7% (27) and 0.10% (1,021) for any advanced neoplasm and cancer, respectively, in men, and 2.1% (47) and 0.05% (1,880) for any advanced neoplasm and cancer, respectively, in women. These NNS values for detecting 1 advanced neoplasm are approximately 3-fold higher, and the NNS values for detecting 1 cancer are approximately 8-fold higher, than those for a first screening colonoscopy at age 55 without prior FITs. This study is limited by model simplifying assumptions and uncertainties related to input parameters.ConclusionsScreening colonoscopy at age 55 after 5 consecutive negative FITs at ages 50-54, as currently offered in the German cancer early detection program, is expected to have very low positive predictive value. Our results may inform efforts to enhance the design of screening programs

Predictors of health-related quality of life in Bavarian preschool children

Background: Little data is available on health-related quality of life (HRQOL) of children in Germany at the age of school enrollment. Objective: The aims of this study were to investigate the HRQOL of children during school enrollment and to determine its predictors with a special focus on environmental factors. Methods: Analyzed data stem from the fifth survey of the Health-Monitoring-Units (GME) conducted in Bavaria. The survey collected data in 2010/2011. Parent-reported data on HRQOL using the KINDL-R(evised), the Strength and Difficulties Questionnaire (SDQ), socio-demographic characteristics and characteristics of the living environment were assessed. Results: The sample under analysis included a total of 3,744 children (45.9% female; mean age was 6.0; SD=0.4). Girls had significant higher values than boys in total HRQOL (83.7 vs. 82.4, p≤0.0001) and in all KINDL-R subscales except “psychological well-being” and “physical well-being”. For the latter, boys had significantly higher values than girls (84.1 vs. 82.9, p≤0.0103). Multiple linear regression analysis showed that parental annoyance with air or noise pollution, children’s possibility to safely play outside and the time a child is outside on weekdays in the summertime were significant predictors of total HRQOL measured by the KINDL-R. Obesity was not linked to HRQOL. Migration background of the child had a positive association with the subscales “family” and “friends”. Conclusions: Environmental factors are associated with HRQOL in children at the age of school enrollment but only partially of relevant use. Although they show significant associations, their explanatory power of the variability observed is rather limited.JRC.C.5-Air and Climat

Consistent Major Differences in Sex- and Age-Specific Diagnostic Performance among Nine Faecal Immunochemical Tests Used for Colorectal Cancer Screening

Evidence on diagnostic performance of faecal immunochemical tests (FITs) by sex and age is scarce. We aimed to evaluate FIT performance for detection of advanced colorectal neoplasia (AN) by sex and age across nine different FIT brands in a colonoscopy-controlled setting. The faecal samples were obtained from 2042 participants of colonoscopy screening. All eligible cases with AN (n = 216) and 300 randomly selected participants without AN were included. Diagnostic performance for detection of AN was assessed by sex and age (50–64 vs. 65–79 years for each of the nine FITs individually and for all FITs combined. Sensitivity was consistently lower, and specificity was consistently higher for females as compared with males (pooled values at original FIT cutoffs, 25.7% vs. 34.6%, p = 0.12 and 96.2% vs. 90.8%, p &lt; 0.01, respectively). Positive predictive values (PPVs) were similar between both sexes, but negative predictive values (NPVs) were consistently higher for females (pooled values, 91.8% vs. 86.6%, p &lt; 0.01). Sex-specific cutoffs attenuated differences in sensitivities but increased differences in predictive values. According to age, sensitivities and specificities were similar, whereas PPVs were consistently lower and NPVs were consistently higher for the younger participants. A negative FIT is less reliable in ruling out AN among men than among women and among older than among younger participants. Comparisons of measures of diagnostic performance among studies with different sex or age distributions should be interpreted with caution

Study protocol of the RaPS study: novel risk adapted prevention strategies for people with a family history of colorectal cancer

Abstract Background People aged 40–60 years with a family history (FH) of colorectal cancer (CRC) in 1st degree relatives (FDRs) have a 2- to 4-fold increased risk of CRC compared to the average risk population. Therefore, experts recommend starting CRC screening earlier for this high-risk group. However, information on prevalence of relevant colonoscopic findings in this group is sparse, and no risk adapted screening offers are implemented in the German health care system. For example, screening colonoscopy is uniformly offered from age 55 on, regardless of family history. Thus, we initiated a multicenter epidemiological study - the RaPS study (Risk adapted prevention strategies for colorectal cancer) – with the following aims: to determine the prevalence of having a FH of CRC in FDR in the German population aged 40–54 years; to investigate the prevalence of colorectal neoplasms among people with a FDR; and to develop risk-adapted prevention strategies for this high-risk group based on the collected information. Methods/Design A random sample of 160.000 persons from the general population aged 40–54 years from the catchment areas of three study centers in Germany (Dresden, Munich and Stuttgart) are contacted to assess FH of CRC by an online-questionnaire. Those with a FH of CRC in FDRs are invited to the study centers for individual consultation regarding CRC prevention. Participants are asked to donate blood and stool samples and medical records of colonoscopies will be obtained. Prevalence of CRC and its precursors will be evaluated. Furthermore, genetic, epigenetic and proteomic biomarkers in blood and microbiomic biomarkers in stool will be investigated. Risk markers and their eligibility for risk adapted screening offers will be examined. Discussion This study will provide data on the prevalence of colorectal neoplasms among persons with a FH of CRC in the age group 40–54 years, which will enable us to derive evidence based screening strategies for this high-risk group. Trial registration This trial was registered retrospectively in the German Clinical Trials Register (DRKS) on 29th of December 2016: German Clinical Trials Register DRKS-ID: DRKS00007842