Combined Performance of Fecal Immunochemical Tests and a Genetic Risk Score for Advanced Neoplasia Detection.

Fecal immunochemical tests (FITs) are increasingly used as noninvasive screening tests in colorectal cancer-screening programs. Polygenic risk scores (PRS) are increasingly propagated for risk stratification in colorectal cancer screening. We aimed to assess the potential of combining FIT results and PRS to enhance diagnostic accuracy of detecting advanced neoplasia (AN) compared with using FIT results alone. Of 10,362 participants of screening colonoscopy in Southern Germany who conducted either one of two quantitative FITs, genotyping was done in all participants with AN (colorectal cancer or advanced adenoma) and a random subset of controls. Among 5,306 individuals, a PRS was calculated on the basis of the number of risk alleles in 140 SNPs. Partial areas under the receiver operating characteristics (ROC) curves (pAUCs) were computed for FIT and PRS alone and combined, focusing on a specificity range of 100%-80%. Both FITs showed similar performance characteristics with pAUCs of 0.661 (95% confidence interval (CI), 0.625-0.698; Ridascreen Hemoglobin) and 0.682 (95% CI, 0.661-0.701; FOB Gold) for AN detection. PRS alone reached a pAUC of 0.524 (95% CI, 0.499-0.550) and 0.530 (95% CI, 0.516-0.545), respectively, and its addition to FIT did not improve pAUCs (0.659; 95% CI, 0.622-0.697) and 0.667 (95% CI, 0.650-0.687), respectively. This finding was confirmed by investigating sensitivities at fixed specificities at 85%, 90%, and 95%. Partial AUCs also did not improve when adding the weighted PRS to FIT instead of the unweighted PRS. In summary, the combination with PRS did not improve diagnostic accuracy of FIT-based screening in a large asymptomatic colorectal cancer screening population from South-Western Germany. PREVENTION RELEVANCE: In our study, combining polygenic risk score with fecal immunochemical test (FIT) did not improve diagnostic accuracy for advanced colorectal neoplasia detection compared with FIT alone. So far, such a combination cannot be recommended because it would come at extra costs and effort despite no relevant gain in neoplasia detection.

Variation of Positive Predictive Values of Fecal Immunochemical Tests by Polygenic Risk Score in a Large Screening Cohort.

INTRODUCTION: Prevalence of colorectal neoplasms varies by polygenic risk scores (PRS). We aimed to assess to what extent a PRS might be relevant for defining personalized cutoff values for fecal immunochemical tests (FITs) in colorectal cancer screening. METHODS: Among 5,306 participants of screening colonoscopy who provided a stool sample for a quantitative FIT (Ridascreen Hemoglobin or FOB Gold) before colonoscopy, a PRS was determined, based on the number of risk alleles in 140 single nucleotide polymorphisms. Subjects were classified into low, medium, and high genetic risk of colorectal neoplasms according to PRS tertiles. We calculated positive predictive values (PPVs) and numbers needed to scope (NNS) to detect 1 advanced neoplasm (AN) by the risk group, and cutoff variation needed to achieve comparable PPVs across risk groups in the samples tested with Ridascreen (N = 1,271) and FOB Gold (N = 4,035) independently, using cutoffs yielding 85%, 90%, or 95% specificity. RESULTS: Performance of both FITs was very similar within each PRS group. For a given cutoff, PPVs were consistently higher by 11%-15% units in the high-risk PRS group compared with the low-risk group (all P values < 0.05). Correspondingly, NNS to detect 1 advanced neoplasm varied from 2 (high PRS, high cutoff) to 5 (low PRS, low cutoff). Conversely, very different FIT cutoffs would be needed to ensure comparable PPVs across PRS groups. DISCUSSION: PPVs and NNS of FITs varied widely across people with high and low genetic risk score. Further research should evaluate the relevance of these differences for personalized colorectal cancer screening.

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 < 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 < 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.

Individual and Joint Associations of Genetic Risk and Healthy Lifestyle Score with Colorectal Neoplasms Among Participants of Screening Colonoscopy.

Genetic and lifestyle factors contribute to colorectal cancer risk. We investigated their individual and joint associations with various stages of colorectal carcinogenesis. We assessed associations of a polygenic risk score (PRS) and a healthy lifestyle score (HLS) with presence of nonadvanced adenomas and advanced neoplasms among 2,585 participants of screening colonoscopy from Germany. The PRS and HLS individually showed only weak associations with presence of nonadvanced adenomas; stronger associations were observed with advanced neoplasms (ORs, 95% CI, for highest vs. lowest risk tertile: PRS 2.27, 1.78-2.88; HLS 1.96, 1.53-2.51). The PRS was associated with higher odds of advanced neoplasms among carriers of any neoplasms (1.65, 1.23-2.22). Subjects in the highest risk tertile (vs. lowest tertile) of both scores had higher risks for nonadvanced adenomas (1.77, 1.09-2.86), for advanced neoplasms (3.95, 2.53-6.16) and, among carriers of any neoplasms, for advanced versus nonadvanced neoplasms (2.26, 1.31-3.92). Both scores were individually associated with increased risk of nonadvanced adenomas and, much more pronounced, advanced neoplasms. The similarly strong association in relative terms across all levels of genetic risk implies that a healthy lifestyle may be particularly beneficial in those at highest genetic risk, given that the same relative risk reduction in this group would imply a stronger absolute risk reduction. Genetic factors may be of particular relevance for the transition of nonadvanced to advanced adenomas. PREVENTION RELEVANCE: Genetic factors have strong impact on the risk of colorectal neoplasms, which may be reduced by healthy lifestyle. Similarly strong associations in relative terms across all levels of genetic risk imply that a healthy lifestyle may be beneficial due to higher absolute risk reduction in those at highest genetic risk.

Genotype-Based Gene Expression in Colon Tissue-Prediction Accuracy and Relationship with the Prognosis of Colorectal Cancer Patients.

Colorectal cancer (CRC) survival has environmental and inherited components. The expression of specific genes can be inferred based on individual genotypes-so called expression quantitative trait loci. In this study, we used the PrediXcan method to predict gene expression in normal colon tissue using individual genotype data from 91 CRC patients and examined the correlation ρ between predicted and measured gene expression levels. Out of 5434 predicted genes, 58% showed a negative ρ value and only 16% presented a ρ higher than 0.10. We subsequently investigated the association between genotype-based gene expression in colon tissue for genes with ρ > 0.10 and survival of 4436 CRC patients. We identified an inverse association between the predicted expression of ARID3B and CRC-specific survival for patients with a body mass index greater than or equal to 30 kg/m2 (HR (hazard ratio) = 0.66 for an expression higher vs. lower than the median, p = 0.005). This association was validated using genotype and clinical data from the UK Biobank (HR = 0.74, p = 0.04). In addition to the identification of ARID3B expression in normal colon tissue as a candidate prognostic biomarker for obese CRC patients, our study illustrates the challenges of genotype-based prediction of gene expression, and the advantage of reassessing the prediction accuracy in a subset of the study population using measured gene expression data.

Polymorphisms in the Angiogenesis-Related Genes EFNB2, MMP2 and JAG1 Are Associated with Survival of Colorectal Cancer Patients.

An individual's inherited genetic variation may contribute to the 'angiogenic switch', which is essential for blood supply and tumor growth of microscopic and macroscopic tumors. Polymorphisms in angiogenesis-related genes potentially predispose to colorectal cancer (CRC) or affect the survival of CRC patients. We investigated the association of 392 single nucleotide polymorphisms (SNPs) in 33 angiogenesis-related genes with CRC risk and survival of CRC patients in 1754 CRC cases and 1781 healthy controls within DACHS (Darmkrebs: Chancen der Verhütung durch Screening), a German population-based case-control study. Odds ratios and 95% confidence intervals (CI) were estimated from unconditional logistic regression to test for genetic associations with CRC risk. The Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% CIs for survival. Multiple testing was adjusted for by a false discovery rate. No variant was associated with CRC risk. Variants in EFNB2, MMP2 and JAG1 were significantly associated with overall survival. The association of the EFNB2 tagging SNP rs9520090 (p < 0.0001) was confirmed in two validation datasets (p-values: 0.01 and 0.05). The associations of the tagging SNPs rs6040062 in JAG1 (p-value 0.0003) and rs2241145 in MMP2 (p-value 0.0005) showed the same direction of association with overall survival in the first and second validation sets, respectively, although they did not reach significance (p-values: 0.09 and 0.25, respectively). EFNB2, MMP2 and JAG1 are known for their functional role in angiogenesis and the present study points to novel evidence for the impact of angiogenesis-related genetic variants on the CRC outcome.

Risk-Adapted Cutoffs in Colorectal Cancer Screening by Fecal Immunochemical Tests.

INTRODUCTION: Fecal immunochemical tests (FITs) for hemoglobin are increasingly used in colorectal cancer (CRC) screening. The use of uniform positivity thresholds (cutoffs) within screening populations is expected to imply lower positive predictive values (PPVs) and higher numbers of colonoscopies needed (numbers needed to scope [NNSs]) to detect advanced neoplasms among screening participants at lower risk compared with those at higher risk. We aimed to assess such variation and its potential implications in a large screening cohort. METHODS: A quantitative FIT (FOB Gold; Sentinel Diagnostics, Milan, Italy) was conducted in fecal samples collected by 4,332 participants of screening colonoscopy before bowel preparation. Participants were classified into 3 risk groups (low, medium, and high) by tertiles of a previously derived risk-factor-based risk score. We determined the variation of PPVs and NNSs for detecting advanced neoplasms (i.e., CRC or advanced adenoma) when using the same FIT cutoffs and variation of FIT cutoffs that would yield uniform PPVs across risk groups. RESULTS: When a fixed FIT cutoff of 10 µg/g was used, the PPV increased from 23.3% to 41.8% from the low- to the high-risk group, with NNS decreasing from 4.3 to 2.4 (P < 0.001). Similar variations of PPVs and NNSs across risk groups were observed at higher FIT cutoffs. When risk group-specific cutoffs were defined to achieve fixed PPVs of 25%, 30%, and 35% across all risk groups, cutoffs varied from 5.3 to 11.4, 6.5 to 18.7, and 7.5 to 31.0 µg hemoglobin/g feces, respectively, between high- and low-risk groups (P < 0.05 for all differences). DISCUSSION: Using risk-adapted cutoffs may help to achieve target levels of PPV and NNS and might be an option to consider for personalized FIT-based CRC screening.

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

BACKGROUND: The 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 FINDINGS: Using 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. CONCLUSIONS: Screening 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.

Use of Polygenic Risk Scores to Select Screening Intervals After Negative Findings From Colonoscopy.

BACKGROUND & AIMS: Polygenic risk scores (PRSs) could help to define starting ages for colorectal cancer (CRC) screening. However, the role of PRS in determining the length of screening interval after negative findings from colonoscopies is unclear. We aimed to evaluate CRC risk according to PRS and time since last negative colonoscopy. METHODS: We collected data from 3827 cases and 2641 CRC-free controls in a population-based case-control study in Germany. We constructed a polygenic risk scoring system, based on 90 single-nucleotide polymorphisms, associated with risk of CRC in people of European descent. Participants were classified as having low, medium, or high genetic risk according to tertiles of PRSs among controls. Multiple logistic regression models were used to assess CRC risk according to PRS and time since last negative colonoscopy. RESULTS: Compared to individuals without colonoscopy in the low PRS category, a 42%-85% lower risk of CRC was observed for individuals who had a negative finding from colonoscopy within 10 years. Beyond 10 years after a negative finding from colonoscopy, significantly lower risk only persisted for the low and medium PRS groups, but not for the high PRS group. Adjusted odds ratios were 0.44 (95% CI, 0.29-0.68), 0.51 (95% CI, 0.34-0.77), and 0.85 (95% CI, 0.58-1.23) in the low, medium, and high PRS group, respectively. Within any time interval, risks were lower for distal than for proximal CRCs. CONCLUSIONS: Based on findings from a population-based case-control study, the recommended 10-year screening interval for colonoscopy may not need to be shortened among people with high PRSs, but could potentially be prolonged for people with low and medium PRSs. Studies are needed to address personalized time intervals for repeat colonoscopies in average-risk screening cohorts.

Impact of Inadequate Bowel Cleansing on Colonoscopic Findings in Routine Screening Practice.

INTRODUCTION: Colonoscopy is an imperfect gold standard for detecting colorectal neoplasms because some proportion of adenomas may be missed, mainly small lesions. This proportion is expected to be higher in case of inadequate bowel cleansing, which is frequently seen in routine practice. We estimated the proportions of neoplasms that are in principle detectable by colonoscopy but might be missed in case of incomplete bowel preparation. METHODS: For 8,193 participants of screening colonoscopy in South-Western Germany, recruited between 2005 and 2016, the prevalence and numbers of different findings were extracted from colonoscopy reports and compared according to the reported bowel preparation quality. RESULTS: Bowel preparation quality was reported as good, poor, or was unspecified in 30.3%, 11.1%, and 58.6% of colonoscopy records. Reported prevalences of nonadvanced adenomas (NAAs) were similar among participants with poor and unspecified bowel preparation quality but substantially lower than among participants with good bowel preparation (adjusted prevalence rate ratio [RR] 0.86, 95% confidence interval [CI]: 0.77-0.96). The differences were observed for proximal but not for distal NAAs (RRs 0.82, 95% CI: 0.71-0.95 and 0.95, 95% CI: 0.82-1.10). DISCUSSION: Our study suggests that a significant proportion of NAAs located in the proximal colon might be missed during colonoscopy if bowel cleansing is not adequate. Major efforts should be made to further facilitate and enhance high-quality bowel preparation in routine screening practice.

[Occurrence of bronchial asthma and age at initial asthma diagnosis-first results of the German National Cohort]. / Häufigkeit von Asthma bronchiale und Alter bei der Erstdiagnose ­ erste Ergebnisse der NAKO Gesundheitsstudie.

BACKGROUND: Asthma is one of the most common chronic diseases in both children and adults. Asthma first occurring in adulthood (adult-onset asthma, AOA) is associated with poorer prognosis compared to childhood-onset asthma (COA), which urgently calls for more research in this area. The aim of this work was to analyze the data on asthma collected in the German National Cohort and compare it with the German Health Interview and Examination Survey for Adults (DEGS), in particular regarding AOA. MATERIAL AND METHODS: Our analysis was based on the dataset of the main questionnaire at mid-term of the German National Cohort baseline examination, comprising 101,723 participants. Variables considered in the analyses were self-reported diagnosis of asthma, age at first diagnosis, asthma treatment in the past 12 months, age, and sex. RESULTS: In the midterm dataset, 8.7% of women and 7.0% of men in the German National Cohort reported that they had ever been diagnosed with asthma. Approximately one third of participants with asthma received their initial diagnosis before their 18th birthday. COA affected 2.2% of women and 2.8% of men, whereas AOA affected 6.5% of women and 4.2% of men. During the previous 12 months, 33% of COA cases and 60% of AOA cases were medically treated. CONCLUSION: The proportion of persons affected by asthma in the German National Cohort, as well as observed patterns regarding age and gender, corresponds to other data sources such as DEGS. However, in our analysis, the proportion of individuals with AOA was higher than described in the literature. The increase in cumulative asthma diagnoses with age is markedly steeper in younger participants, indicating a rising trend over time.

Estimation of Absolute Risk of Colorectal Cancer Based on Healthy Lifestyle, Genetic Risk, and Colonoscopy Status in a Population-Based Study.

BACKGROUND & AIMS: Estimates of absolute risk of colorectal cancer (CRC) are needed to facilitate communication and better inform the public about the potentials and limits of cancer prevention. METHODS: Using data from a large population-based case-control study in Germany (Darmkrebs: Chancen der Verhütung durch Screening [DACHS] study, which began in 2003) and population registry data, we calculated 30-year absolute risk estimates for development of CRC based on a healthy lifestyle score (derived from 5 modifiable lifestyle factors: smoking, alcohol consumption, diet, physical activity, and body fatness), a polygenic risk score (based on 90 single-nucleotide polymorphisms), and colonoscopy history. RESULTS: We analyzed data from 4220 patients with CRC and 3338 individuals without CRC. Adherence to a healthy lifestyle and colonoscopy in the preceding 10 years were associated with a reduced relative risk of CRC in men and women. We observed a higher CRC risk in participants with high or intermediate genetic risk scores. For 50-year-old men and women without a colonoscopy, the absolute risk of CRC varied according to the polygenic risk score and the healthy lifestyle score (men, 3.5%-13.4%; women, 2.5%-10.6%). For 50-year-old men and women with a colonoscopy, the absolute risk of developing CRC was much lower but still varied according to the polygenic risk score and the healthy lifestyle score (men, 1.2%-4.8%; women, 0.9%-4.2%). Among all risk factor profiles, the 30-year absolute risk estimates consistently decreased with adherence to a healthy lifestyle. CONCLUSIONS: In a population-based study, we found that a colonoscopy can drastically reduce the absolute risk of CRC and that the genetically predetermined risk of CRC can be further reduced by adherence to a healthy lifestyle. Our results show the magnitude of CRC prevention possible through colonoscopy and lifestyle at a predefined genetic risk. This observational study has been registered in the German Clinical Trials Register (DRKS00011793), which is a primary registry in the World Health Organization Registry Network.

Multiplex quantitation of 270 plasma protein markers to identify a signature for early detection of colorectal cancer.

Blood-based protein biomarker signatures might be an alternative or supplement to existing methods for early detection of colorectal cancer (CRC) for population-based screening. The objective of this study was to derive a protein biomarker signature for early detection of CRC and its precursor advanced adenoma (AA). In a two-stage design, 270 protein markers were measured by liquid chromatography/multiple reaction monitoring/mass spectrometry in plasma samples of discovery and validation sets. In the discovery set consisting of 100 newly diagnosed CRC cases and 100 age- and sex-matched controls free of neoplasm at screening colonoscopy, the algorithms predicting the presence of early- or late-stage CRC were derived by Lasso regression and .632 + bootstrap. The prediction algorithms were then externally validated in an independent validation set consisting of participants of screening colonoscopy including 56 participants with CRC, 99 with AA and 99 controls without any colorectal neoplasms. Three different signatures for all-, early- and late-stage CRC consisting of five-, three- and eight-protein markers were obtained in the discovery set with areas under the curves (AUCs) after .632 + bootstrap adjustment of 0.85, 0.83 and 0.96, respectively. External validation in the representative screening population yielded AUCs of 0.79 (95% CI, 0.70-0.86), 0.79 (95% CI, 0.66-0.89) and 0.80 (95% CI, 0.70-0.89) for all-, early- and late-stage CRCs, respectively. The three-marker early-stage algorithm yielded an AUC of 0.65 (95% CI, 0.56-0.73) for detection of AA in the validation set. Although not yet competitive with available stool-based tests for CRC early detection, the identified proteins may contribute to the development of powerful blood-based tests for early detection of CRC and its precursors AAs.

Prevalence of a First-Degree Relative With Colorectal Cancer and Uptake of Screening Among Persons 40 to 54 Years Old.

BACKGROUND & AIMS: People with a first-degree relative with colorectal cancer (CRC) are recommended to start CRC screening at age 40. However, there is limited information on how many people in different age groups have a known family history of CRC and how many of them have had a colonoscopy. METHODS: We set up a multicenter, cross-sectional, population-based study in Germany to determine what proportions of persons in age groups from 40 to 54 years old have a known family history of CRC. We invited 160,000 persons to participate in an online survey from 2015 through 2016. We investigated what proportions of persons in each age group reported a family history of CRC and what proportions of persons underwent a colonoscopy examination using descriptive statistics and multiple logistic regression models. RESULTS: Of 28,711 responders to the online questionnaire (8428 were age 40-44 years, 9879 were age 45-49 years, and 10,404 were age 50-54 years), 2705 stated that they had a first-degree relative with CRC (9.4%). The prevalence of a first-degree relative with CRC increased with age: 7.5%, 9.6%, and 10.9% for people 40 to 44 years old, 45 to 49 years old, and 50 to 54 years old, respectively. The prevalence of a first-degree relative who received a diagnosis of CRC at age 70 years or older increased steadily with each age group. Although a greater proportion of people with a family history of CRC had undergone a colonoscopy examination (54.5%) than people without a family history of CRC (25.7%; P < .0001), large proportions of people within this risk group were not in compliance with the guidelines (54.8%, 47.6%, and 38.6% for ages 40-44 y, 45-49 y, and 50-54 y, respectively). CONCLUSIONS: One in 10 persons in Germany age 40 to 54 years old has a first-degree relative with CRC. Guidelines recommend initiation of screening at ages 40 to 45 years for people with a family history, yet at this age many people do not have a family history of CRC yet, and almost half of persons 40 to 54 years old with a family history of CRC have not yet received a screening colonoscopy.

Performance of individual and joint risk stratification by an environmental risk score and a genetic risk score in a colorectal cancer screening setting.

Early detection of colorectal neoplasms can reduce the disease burden of colorectal cancer by timely intervention of individuals at high risk. Our aim was to evaluate a joint environmental-genetic risk score as a risk stratification tool for early detection of advanced colorectal neoplasm (ACRN). Known environmental risk factors and high-risk genetic loci were summarized into risk scores for ACRN in 1014 eligible participants of a screening study. The performances of single and joint environmental-genetic scores were evaluated with estimates and 95% confidence intervals (CI) of the absolute risk, relative risk and predictive ability using the area under the curve (AUC). Individuals with higher environmental risk scores showed increasing ACRN risk, with 3.1-fold for intermediate risk and 4.8-fold for very high risk, compared to the very low environmental risk group. Similarly, individuals with higher genetic risk scores showed increasing ACRN risk, with 2.2-fold for intermediate risk and 3.5-fold for very high risk, compared to the lowest genetic risk group. Moreover, the joint environmental-genetic score improved the ACRN risk stratification and showed higher predictive values (AUC = 0.64; 95%CI = 0.60-0.67) with substantial difference (p = 0.0002) compared to the single environmental score (0.58; 0.55-0.62). The integration of environmental and genetic factors looks promising for improving targeting individuals at high-risk of colorectal neoplasm. Applications in practical screening programs require optimization with additional genetic and other biomarkers involved in colorectal carcinogenesis.

Establishing a valid approach for estimating familial risk of cancer explained by common genetic variants.

We critically examined existing approaches for the estimation of the excess familial risk of cancer that can be attributed to identified common genetic risk variants and propose an alternative, more straightforward approach for calculating this proportion using well-established epidemiological methodology. We applied the underlying equations of the traditional approaches and the new epidemiological approach for colorectal cancer (CRC) in a large population-based case-control study in Germany with 4,447 cases and 3,480 controls, who were recruited from 2003 to 2016 and for whom interview, medical and genomic data were available. Having a family history of CRC (FH) was associated with a 1.77-fold risk increase in our study population (95% CI 1.52-2.07). Traditional approaches yielded estimates of the FH-associated risk explained by 97 common genetics variants from 9.6% to 23.1%, depending on various assumptions. Our alternative approach resulted in smaller and more consistent estimates of this proportion, ranging from 5.4% to 14.3%. Commonly employed methods may lead to strongly divergent and possibly exaggerated estimates of excess familial risk of cancer explained by associated known common genetic variants. Our results suggest that familial risk and risk associated with known common genetic variants might reflect two complementary major sources of risk.

Multiplex screening of 275 plasma protein biomarkers to identify a signature for early detection of colorectal cancer.

Blood-based protein biomarkers may be an attractive option for early detection of colorectal cancer (CRC). Here, we used a two-stage design to measure 275 protein markers by proximity extension assay (PEA), first in plasma samples of a discovery set consisting of 98 newly diagnosed CRC cases and 100 age- and gender-matched controls free of neoplasm at screening colonoscopy. An algorithm predicting the presence of early- or late-stage CRC was derived by least absolute shrinkage and selection operator regression with .632+ bootstrap method, and the algorithms were then validated using PEA again in an independent validation set consisting of participants of screening colonoscopy with and without CRC (n = 56 and 102, respectively). Three different signatures for all-, early-, and late-stage CRC consisting of 9, 12, and 11 protein markers were obtained in the discovery set with areas under the curves (AUCs) after .632 + bootstrap adjustment of 0.92, 0.91, and 0.96, respectively. External validation among participants of screening colonoscopy yielded AUCs of 0.76 [95% confidence interval (95% CI), 0.67-0.84], 0.75 (95% CI, 0.62-0.87), and 0.80 (95% CI, 0.68-0.89) for all-, early-, and late-stage CRC, respectively. Although the identified protein markers are not competitive with the best available stool tests, these proteins may contribute to the development of powerful blood-based tests for CRC early detection in the future.

Individual and joint performance of DNA methylation profiles, genetic risk score and environmental risk scores for predicting breast cancer risk.

DNA methylation patterns in the blood, genetic risk scores (GRSs), and environmental risk factors can potentially improve breast cancer (BC) risk prediction. We assessed the individual and joint predictive performance of methylation, GRS, and environmental risk factors for BC incidence in a prospective cohort study. In a cohort of 5462 women aged 50-75 from Germany, 101 BC cases were identified during 14 years of follow-up and were compared to 263 BC-free controls in a nested case-control design. Three previously suggested methylation risk scores (MRSs) based on methylation of 423, 248, and 131 cytosine-phosphate-guanine (CpG) loci, and a GRS based on the risk alleles from 269 recently identified single nucleotide polymorphisms were constructed. Additionally, multiple previously proposed environmental risk scores (ERSs) were built based on environmental variables. Areas under the receiver operating characteristic curves (AUCs) were estimated for evaluating BC risk prediction performance. MRS and ERS showed limited accuracy in predicting BC incidence, with AUCs ranging from 0.52 to 0.56 and from 0.52 to 0.59, respectively. The GRS predicted BC incidence with a higher accuracy (AUC = 0.61). Adjusted odds ratios per standard deviation increase (95% confidence interval) were 1.07 (0.84-1.36) and 1.40 (1.09-1.80) for the best performing MRS and ERS, respectively, and 1.48 (1.16-1.90) for the GRS. A full risk model combining the MRS, GRS, and ERS predicted BC incidence with the highest accuracy (AUC = 0.64) and might be useful for identifying high-risk populations for BC screening.

Effect of long-term frozen storage and thawing of stool samples on faecal haemoglobin concentration and diagnostic performance of faecal immunochemical tests.

Background Faecal samples collected and stored frozen over years may be a valuable resource for efficient retrospective evaluation of faecal immunochemical tests (FITs). We aimed to assess how prolonged frozen storage and freeze-thaw cycles might affect measures of faecal haemoglobin (Hb) and diagnostic performance of FITs. Methods From 2005 through 2010, participants of screening colonoscopy (n = 2042) and clinical colorectal cancer (CRC) cases (n = 184) provided faecal samples in stool containers (60 mL). The samples were stored at -80 °C for up to 11 years and underwent three freeze-thaw cycles. Between each cycle, a defined amount of faeces was extracted using the manufacturer's sampling device of one or two FITs (RIDASCREEN, OC-Sensor). Faecal Hb concentration and diagnostic performance were calculated and compared across freeze-thaw cycles. Results For RIDASCREEN and the OC-Sensor, repeat measurements were available for 504 and 551 study participants, respectively. Hb concentrations correlated strongly (0.77 and 0.85, respectively) and diagnostic performance indicators were similar at the repeat measurements among the same FITs. For RIDASCREEN we found even slightly higher Hb levels, sensitivities and area under the curves (AUCs) after the third than after the first freeze-thaw cycle. For the OC-Sensor the Hb levels, sensitivities and AUCs were slightly lower after prolonged storage and one additional freeze-thaw cycle. Conclusions Measures of Hb and diagnostic performance were fairly stable, even after long-term frozen storage and multiple freeze-thaw cycles of raw faecal samples. Faecal samples collected in prospective screening studies and kept frozen at -80 °C before analysis seem useful for timely and efficient retrospective evaluation of FIT performance.