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Simple Summary: After getting treated for colorectal cancer, many people feel fatigue, stress, and pain and face other challenges that can make daily activities and work tough. Our research explored how these issues group together and if they are connected to fatigue and difficulties in work. We gathered data from the MIRANDA study, where patients shared their experiences after colorectal cancer treatment before the start of the rehabilitation and three months after. Using data from their questionnaire responses, we identified six main problem groups: fatigue, digestive troubles, pain, feelings of stress or anxiety, urinary issues, and side effects from chemotherapy. Our findings reveal that experiencing even a single symptom from these categories can be a precursor to feeling more fatigued or having a decreased ability to work. Our findings shed light on colorectal cancer survivors' various challenges and how they might impact their daily lives and work. In colorectal cancer (CRC) patients, apart from fatigue, psychological and physical symptoms often converge, affecting their quality of life and ability to work. Our objective was to ascertain symptom clusters within a year following CRC treatment and their longitudinal association with persistent fatigue and reduced work ability at the 3-month follow-up. We used data from MIRANDA, a multicenter cohort study enrolling adult CRC patients who are starting a 3-week in-patient rehabilitation within a year post-curative CRC treatment. Participants completed questionnaires evaluating symptoms at the start of rehabilitation (baseline) and after three months. We performed an exploratory factor analysis to analyze the clustering of symptoms at baseline. Longitudinal analysis was performed using a multivariable linear regression model with dichotomized symptoms at baseline as independent variables, and the change in fatigue and ability to work from baseline to 3-month-follow-up as separate outcomes, adjusted for covariates. We identified six symptom clusters: fatigue, gastrointestinal symptoms, pain, psychosocial symptoms, urinary symptoms, and chemotherapy side effects. At least one symptom from each factor was associated with higher fatigue or reduced ability to work at the 3-month follow-up. This study highlights the interplay of multiple symptoms in influencing fatigue and work ability among CRC patients post-rehabilitation. [ABSTRACT FROM AUTHOR]

Simple Summary: Carcinoembryonic antigen (CEA) in serum is widely used as a tumor marker in colorectal cancer (CRC). The levels of fecal CEA (FCEA) are higher than serum CEA (SCEA), especially in the early stages of CRC. In this systematic review, we aimed to provide a comprehensive overview of studies that evaluated FCEA as a biomarker for the noninvasive diagnosis and diagnosis of CRC. All of the few identified studies found statistically significant differences in FCEA levels between the CRC and control groups. Moreover, the diagnostic performance of FCEA surpassed that of SCEA, suggesting a potential role as a novel, easily measurable biomarker for the diagnosis of CRC. However, evidence is still limited to a few, mostly small, studies from clinical settings, and comprehensive evaluation in screening settings is warranted. Carcinoembryonic antigen (CEA) is more abundant in feces than in serum; however, evidence for the role of fecal CEA (FCEA) in the detection of colorectal cancer (CRC) is limited. We conducted a systematic review of studies that evaluated FCEA for the noninvasive detection and diagnosis of CRC. PubMed and Web of Science were searched for relevant studies published until 18 January 2023. Information on publication year, study design, country, study population characteristics, FCEA and serum CEA (SCEA) concentrations, and diagnostic performance was summarized. Two authors independently extracted data and assessed the risk of bias and applicability of each included study. Seven studies published between 1979 and 2021, all conducted in clinical settings and together involving 399 CRC patients and 889 controls, were identified. Significant differences in FCEA concentrations were observed between CRC and control groups in all studies. Methods for detecting FCEA varied, with the electronic chemiluminescence immunoassay (ECLIA) being used in the most recent studies. Reported sensitivities, specificities, and area under the curves of FCEA ranged from 50.0% to 85.7%, 73.0% to 100.0%, and 0.704 to 0.831, respectively. In direct comparisons, the diagnostic performance of FCEA was better than that of SCEA. The potential role of FCEA as a novel, noninvasive, easily measurable biomarker for the diagnosis of CRC requires further evaluation in screening settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Platelets express the C-type lectin-like receptor 2 (CLEC-2) that enables binding to podoplanin (PDPN)-expressing tumor cells and, thereby, promote metastatic spread. An increased level of soluble CLEC-2 was reported in patients with thromboinflammatory and malignant disease, presumably released from activated platelets. In our study, we show that in vitro platelet activation leads to a significant decrease in CLEC-2 on platelets and in the plasma. We also found decreased levels of soluble CLEC-2 in plasma samples of patients with colorectal carcinoma (stages I to IV), breast cancer or melanoma (stages I to III) compared to healthy donors. Interestingly, in patients with glioblastoma, the plasma level of soluble CLEC-2 was significantly higher. We concluded that an increased plasma level of soluble CLEC-2 is not a suitable biomarker of platelet activation and tumor progression in most types of cancer. The C-type lectin-like receptor 2 (CLEC-2) is expressed on platelets and mediates binding to podoplanin (PDPN) on various cell types. The binding to circulating tumor cells (CTCs) leads to platelet activation and promotes metastatic spread. An increased level of soluble CLEC-2 (sCLEC-2), presumably released from activated platelets, was shown in patients with thromboinflammatory and malignant disease. However, the functional role of sCLEC-2 and the mechanism of sCLEC-2 release are not known. In this study, we focused on the effect of platelet activation on CLEC-2 expression and the sCLEC-2 plasma level in patients with cancer. First, citrated blood from healthy volunteer donors (n = 20) was used to measure the effect of platelet stimulation by classical agonists and PDPN on aggregation, CLEC-2 expression on platelets with flow cytometry, sCLEC-2 release to the plasma with ELISA and total CLEC-2 expression with Western blot analysis. Second, sCLEC-2 was determined in plasma samples from healthy donors (285) and patients with colorectal carcinoma (CRC; 194), melanoma (160), breast cancer (BC; 99) or glioblastoma (49). PDPN caused a significant increase in the aggregation response induced by classical agonists. ADP or PDPN stimulation of platelets caused a significant decrease in CLEC-2 on platelets and sCLEC-2 in the plasma, whereas total CLEC-2 in platelet lysates remained the same. Thus, the increased plasma level of sCLEC-2 is not a suitable biomarker of platelet activation. In patients with CRC (median 0.9 ng/mL), melanoma (0.9 ng/mL) or BC (0.7 ng/mL), we found significantly lower sCLEC-2 levels (p < 0.0001), whereas patients with glioblastoma displayed higher levels (2.6 ng/mL; p = 0.0233) compared to healthy controls (2.1 ng/mL). The low sCLEC-2 plasma level observed in most of the tumor entities of our study presumably results from the internalization of sCLEC-2 by activated platelets or binding of sCLEC-2 to CTCs. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) patients often experience fatigue, poor ability to work, and low quality of life (QoL) after therapy. We conducted a prospective study of 147 CRC patients who underwent a three-week in-patient rehabilitation clinic visit in Germany. Patients completed questionnaires at the start of rehabilitation and at regular 3-month intervals for up to a year. We found a strong correlation between fatigue and QoL, and moderate correlations between fatigue and the ability to work, as well as between QoL and the ability to work. Fatigue, QoL, and ability to work improved significantly from the start of rehabilitation to the three-month follow-up, and there was little change afterward in the first year after rehabilitation. In summary, fatigue, QoL, and the ability to work were highly interconnected in CRC patients, and all of them improved from the start of rehabilitation to the 3-month follow-up. Cancer-related fatigue, low quality of life (QoL), and low ability to work are highly prevalent among colorectal cancer (CRC) patients after tumor surgery. We aimed to analyze their intercorrelations and trajectories in the first year after in-patient rehabilitation in the German multicenter MIRANDA cohort study. Recruitment is ongoing, and we included the first 147 CRC patients in this analysis. Participants filled out questionnaires at the beginning of in-patient rehabilitation (baseline) and at 3, 6, 9, and 12 months after the baseline. The EORTC-QLQ-C30-General-Health-Status (GHS)/QoL, the FACIT-F-Fatigue Scale, and the FACIT-F-FWB-ability-to-work items were used to evaluate QoL, fatigue, and ability to work, respectively. The fatigue and QoL scales were highly correlated (r = 0.606). A moderate correlation was observed between the fatigue and ability to work scales (r = 0.487) and between the QoL and ability to work scales (r = 0.455). Compared to the baseline, a statistically significant improvement in the QoL, ability to work, and fatigue scales were observed at the 3-month follow-up (Wilcoxson signed rank test, all p < 0.0001). The three scales plateaued afterward until the 12-month follow-up. In conclusion, fatigue, QoL, and ability to work were highly interrelated, improved quickly during/after in-patient rehabilitation, and did not change much afterward in German CRC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Screening for colorectal cancer (CRC) has considerably contributed to declining CRC incidence and mortality rates in Germany over the last two decades. However, evidence on the cost-effectiveness of this public health remains scarce, mostly due to the lack of detailed sex- and age-specific estimates on CRC treatment costs over time. Using a large research database on insurance claims data, we analyzed CRC-related inpatient, outpatient as well as medication costs up to five years after diagnosis and prior to death. Our findings show that costs in the terminal phase of care were consistently on a high level even several years preceding death, mostly driven by high inpatient and medication costs, and substantially higher as compared to the initial phase of care. As well, we observed a consistent pattern of higher costs in men versus women, most markedly in the first year of diagnosis and the final year of life, and strongly varying costs by age. Our findings could be highly useful in informing cost-effectiveness analyses e.g., to further optimize strategies to screen for CRC. Objective: Evidence on the cost-effectiveness of screening for colorectal cancer (CRC) in the German general population remains scarce as key input parameters, the costs to treat CRC, are largely unknown. Here, we provide detailed estimates on CRC treatment costs over time. Methods: Using insurance claims data from the Vilua healthcare research database, we included subjects with newly diagnosed CRC and subjects who died of CRC between 2012 and 2016. We assessed annualized CRC-related inpatient, outpatient and medication costs for up to five years after first diagnosis and prior to death, stratified by sex and age. Findings: We identified 1748 and 1117 subjects with follow-up data for at least 1 year after diagnosis and prior to death, respectively. In those newly diagnosed, average costs were highest in the first year after diagnosis (men, EUR 16,375–16,450; women, EUR 10,071–13,250) and dropped steeply in the following years, with no consistent pattern of differences with respect to age. Costs prior to death were substantially higher as compared to the initial phase of care and consistently on a high level even several years before death, peaking in the final year of life, with strong differences by sex and age (men vs. women, <70 years, EUR 34,351 vs. EUR 31,417; ≥70 years, EUR 14,463 vs. EUR 9930). Conclusion: Once clinically manifest, CRC causes substantial treatment costs over time, particularly in the palliative care setting. Strong differences in treatment costs by sex and age warrant further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Selection of appropriate high-risk smokers is one of the major challenges for implementing low-dose computed tomography screening for lung cancer. Many lung cancer risk prediction models have been proposed to supplement lung cancer screening. This study evaluated the potential of inflammatory protein markers to enhance lung cancer risk stratification beyond lung cancer risk models. The addition of inflammatory protein markers to existing lung cancer risk models improved risk prediction. The inflammatory protein markers may enhance current risk stratification and may be useful to identify high-risk populations for lung cancer screening. Randomized trials have demonstrated a substantial reduction in lung cancer (LC) mortality by screening heavy smokers with low-dose computed tomography (LDCT). The aim of this study was to assess if and to what extent blood-based inflammatory protein biomarkers might enhance selection of those at highest risk for LC screening. Ever smoking participants were chosen from 9940 participants, aged 50–75 years, who were followed up with respect to LC incidence for 17 years in a prospective population-based cohort study conducted in Saarland, Germany. Using proximity extension assay, 92 inflammation protein biomarkers were measured in baseline plasma samples of ever smoking participants, including 172 incident LC cases and 285 randomly selected participants free of LC. Smoothly clipped absolute deviation (SCAD) penalized regression with 0.632+ bootstrap for correction of overoptimism was applied to derive an inflammation protein biomarker score (INS) and a combined INS-pack-years score in a training set, and algorithms were further evaluated in an independent validation set. Furthermore, the performances of nine LC risk prediction models individually and in combination with inflammatory plasma protein biomarkers for predicting LC incidence were comparatively evaluated. The combined INS-pack-years score predicted LC incidence with area under the curves (AUCs) of 0.811 and 0.782 in the training and the validation sets, respectively. The addition of inflammatory plasma protein biomarkers to established nine LC risk models increased the AUCs up to 0.121 and 0.070 among ever smoking participants from training and validation sets, respectively. Our results suggest that inflammatory protein biomarkers may have potential to improve the selection of people for LC screening and thereby enhance screening efficiency. [ABSTRACT FROM AUTHOR]

Simple Summary: Previous studies have shown heavy intake of different alcoholic beverages affects prostate cancer (PCa) clinical outcomes differently. However, the intake patterns of specific alcoholic beverages for PCa status are understudied. The study's objective is to evaluate intake patterns of total alcohol and three types of alcoholic beverage (beer, wine, and spirits) by PCa risk and aggressiveness status. This study included 10,029 men with European ancestry (4676 non-PCa men and 5353 PCa patients). We found PCa patients had a similar total heavy alcohol intake compared with non-PCa men. However, PCa patients were likely to drink more wine and spirits than non-PCa men. Patients with aggressive PCa drank more beer but not wine and spirits. Interestingly, heavy wine intake was inversely associated with PCa aggressiveness. These findings suggest that the intake patterns of specific alcoholic beverages differ by PCa status, and this information might help develop personalized alcohol intervention for PCa patients. Background: Previous studies have shown that different alcoholic beverage types impact prostate cancer (PCa) clinical outcomes differently. However, intake patterns of specific alcoholic beverages for PCa status are understudied. The study's objective is to evaluate intake patterns of total alcohol and the three types of beverage (beer, wine, and spirits) by the PCa risk and aggressiveness status. Method: This is a cross-sectional study using 10,029 men (4676 non-PCa men and 5353 PCa patients) with European ancestry from the PCa consortium. Associations between PCa status and alcohol intake patterns (infrequent, light/moderate, and heavy) were tested using multinomial logistic regressions. Results: Intake frequency patterns of total alcohol were similar for non-PCa men and PCa patients after adjusting for demographic and other factors. However, PCa patients were more likely to drink wine (light/moderate, OR = 1.11, p = 0.018) and spirits (light/moderate, OR = 1.14, p = 0.003; and heavy, OR = 1.34, p = 0.04) than non-PCa men. Patients with aggressive PCa drank more beer than patients with non-aggressive PCa (heavy, OR = 1.48, p = 0.013). Interestingly, heavy wine intake was inversely associated with PCa aggressiveness (OR = 0.56, p = 0.009). Conclusions: The intake patterns of some alcoholic beverage types differed by PCa status. Our findings can provide valuable information for developing custom alcohol interventions for PCa patients. [ABSTRACT FROM AUTHOR]

Objective: In order to find low abundant proteins secretome and tumor tissue proteome data have been explored in the last few years for the diagnosis of colorectal cancer (CRC). In this review we aim to summarize the results of studies evaluating markers derived from the secretome and tumor proteome for blood based detection of colorectal cancer. Methods: Observing the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines PubMed and Web of Science databases were searched systematically for relevant studies published up to 18 July 2017. After screening for predefined eligibility criteria a total of 47 studies were identified. Information on diagnostic performance indicators, methodological procedures and validation was extracted. Functions of proteins were identified from the UniProt database and the the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess study quality. Results: Forty seven studies meeting inclusion criteria were identified. Overall, 83 different proteins were identified, with carcinoembryonic Antigen (CEA) being by far the most commonly reported (reported in 24 studies). Evaluation of the markers or marker combinations in blood samples from CRC cases and controls yielded apparently very promising diagnostic performances, with area under the curve >0.9 in several cases, but lack of internal or external validation, overoptimism due to overfitting and spectrum bias due to evaluation in clinical setting rather than screening settings are major concerns. Conclusions: Secretome and tumor proteome-based biomarkers when validated in blood yield promising candidates. However, for discovered protein markers to be clinically applicable as screening tool they have to be specific for early stages and need to be validated externally in larger studies with participants recruited in true screening setting. [ABSTRACT FROM AUTHOR]

Simple Summary: Screening for colorectal cancer is effective for the reduction of both CRC incidence and mortality in the population at average risk. The use of innovative and robust biomarkers to enhance the potential of noninvasive CRC screening remains desirable. We aimed to conduct a systematic literature review on the diagnostic performance of fecal miRNA markers for CRC and its precursors. Several studies have reported quite promising results, in particular by combining fecal miRNA measurements with fecal hemoglobin. However, current evidence is limited by substantial heterogeneity in the methodology from study design to biosample analysis. Our review is intended to provide a valuable reference for future biomarker studies in early colorectal cancer detection. Looking at fecal miRNAs, we draw attention to the various biases to be avoided or at least minimized, by applying a harmonized methodology including true screening settings and comparable sample pre-analytics, as well as the validation of biomarkers. Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer mortality globally. Fecal miRNAs have been suggested to be promising biomarkers for CRC early detection. We aimed to conduct a systematic literature review on the diagnostic performance of fecal miRNA markers for CRC and its precursors. PubMed and Web of Science were searched to retrieve relevant articles published up to 7 December 2021. Information on study design, characteristics of study population, pre-analytics (sample collection, processing, and storage), fecal miRNA extraction and quantification technologies, and diagnostic performance (including sensitivity, specificity, and area under the curve (AUC)) were summarized. Twenty studies reporting on 31 individual miRNAs and 16 miRNA panels (with 2–9 markers) for CRC diagnosis were identified. Substantial heterogeneity existed regarding stool sample collection, processing, storage, and miRNA extraction and normalization. For two individual miRNAs and one miRNA panel, values ≥ 80% were reported for both sensitivity and specificity; however, none of these results were either internally or externally validated. In a study among fecal immunochemical test-positive cases recruited from a true screening setting, better diagnostic performance was identified and internally validated for a combination panel including two miRNAs, fecal hemoglobin level, and patient age and sex, compared with fecal hemoglobin concentration alone. Fecal miRNAs or miRNA panels, possibly in combination with fecal hemoglobin test, may be promising candidates for noninvasive CRC early detection. However, large prospective and well-designed studies in CRC screening cohorts are required to validate promising miRNAs or miRNA panels. [ABSTRACT FROM AUTHOR]

Simple Summary: We evaluated the performance of nine faecal immunochemical tests among participants of screening colonoscopy. A total of 216 cases of advanced neoplasia (AN, colorectal cancer or advanced adenoma) 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 faecal immunochemical tests (FITs) individually and for all FITs combined. Major differences in diagnostic performance by sex and age were consistently seen across nine different FIT brands. Sensitivities were consistently lower, and specificities were consistently higher, for females as compared with males. Positive predictive values were similar between both sexes, but negative predictive values were higher for females. A negative FIT is less reliable in ruling out AN among men than among women and among older than among younger participants. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Inflammation is involved in the evolution of cancer. Leukocytes, of which the proportion can be estimated using epigenome-wide methylation data, may serve as a prognostic marker in colorectal cancer (CRC). Our aim was to investigate whether DNA methylation-based estimates of circulating leukocytes is associated with all-cause and disease-specific mortality in a prospective CRC patients' cohort. Significant associations with CRC prognosis were observed for CD4+ T cells, CD8+ T cells, B cells, NK cells, and lymphocytes, independent of age, sex, tumor stage, tumor subsite, and therapy. CD4+ T cells outperformed other leukocytes and provided added predictive value in comparison to age, sex, and tumor stage. Although cell counting is commonly used in clinical practice, DNA methylation-estimated cell proportions could be a promising tool in understanding the role of leukocytes as CRC prognostic biomarkers when using stored blood samples. Leukocytes are involved in the progression of colorectal cancer (CRC). The proportion of six major leukocyte subtypes can be estimated using epigenome-wide DNA methylation (DNAm) data from stored blood samples. Whether the composition of circulating leukocytes can be used as a prognostic factor is unclear. DNAm-based leukocyte proportions were obtained from a prospective cohort of 2206 CRC patients. Multivariate Cox regression models and survival curves were applied to assess associations between leukocyte composition and survival outcomes. A higher proportion of lymphocytes, including CD4+ T cells, CD8+ T cells, B cells, and NK cells, was associated with better survival, while a higher proportion of neutrophils was associated with poorer survival. CD4+ T cells outperformed other leukocytes in estimating the patients' prognosis. Comparing the highest quantile to the lowest quantile of CD4+ T cells, hazard ratios (95% confidence intervals) of all-cause and CRC-specific mortality were 0.59 (0.48, 0.72) and 0.59 (0.45, 0.77), respectively. Furthermore, the association of CD4+ T cells and prognosis was stronger among patients with early or intermediate CRC or patients with colon cancer. In conclusion, the composition of circulating leukocytes estimated from DNAm, particularly the proportions of CD4+ T cells, could be used as promising independent predictors of CRC survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Little is known about the health-related quality of life in very long-term cancer survivors 10 and more years post-diagnosis. Therefore, we compared the health-related quality of life of survivors of breast, colorectal, and prostate cancer (14–24 years post-diagnosis) with that of same-aged non-cancer controls, according to age, sex, and disease status (disease-free vs. stage IV, recurrence, metastasis, or second cancer). We found that the overall global health status/quality of life of cancer survivors more than a decade after diagnosis was slightly higher than that of population controls of the same age, but more symptoms and lower functioning were reported. Differences were small but statistically significant. Results differed by age, sex, and disease status. The findings point out the need for a comprehensive survivorship care program in order to monitor and treat potential late and long-term effects after the diagnosis and treatment of cancer. Survivorship care should be risk-adapted to survivors' needs according to sociodemographic and clinical factors. (1) Background: Little is known about the health-related quality of life (HRQoL) in very long-term cancer survivors (VLTCS) 10 and more years post-diagnosis. The objective was to compare cancer survivors' HRQoL 14–24 years post-diagnosis with that of same-aged non-cancer controls, stratified by age, sex, and disease status (disease-free vs. stage IV, recurrence, metastasis, or second cancer). (2) Methods: We recruited 2704 very long-term survivors of breast, colorectal and prostate cancer, and 1765 controls in German multi-regional population-based studies. The HRQoL was assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Differences in the HRQoL were estimated with multiple regression, controlling for age, sex (where appropriate), and education. (3) Results: The overall global health status/quality of life of VLTCS more than a decade after diagnosis was slightly higher than that of population controls of the same age, but more symptoms and lower functioning were reported. Differences were small but statistically significant. Results differed by age, sex, and disease status. (4) Conclusions: The findings point out the need for a comprehensive survivorship care program in order to monitor and treat potential late and long-term effects after the diagnosis and treatment of cancer. Survivorship care should be risk-adapted to survivors' needs according to sociodemographic and clinical factors. [ABSTRACT FROM AUTHOR]

Simple Summary: There is large heterogeneity in invitation schemes and participation rates in colorectal cancer screening programs offering fecal occult blood tests (nowadays mostly fecal immunochemical tests). It is unclear what the most effective invitation strategies are for fecal occult blood tests. In this systematic review, advance notification, mailed fecal occult blood test, and reminders had major, consistent, and complementary potential to increase participation in fecal occult blood test-based colorectal cancer screening. Our findings show that the effectiveness of invitations for fecal occult blood test-based colorectal cancer screening can be substantially increased across several settings by the implementation of comprehensive invitation strategies. Personal invitations for fecal occult blood tests (nowadays mostly fecal immunochemical tests) are increasingly used to raise their usage for colorectal cancer screening. However, there is a large heterogeneity in applied invitation schemes. We aimed to review evidence for the effectiveness of various invitation schemes. The main outcome was the fecal occult blood test usage rate. A systematic search was performed in Medline and Web of Science (up to 9 July 2020). Randomized controlled trials or cluster-randomized controlled trials were eligible, which reported on general invitations for fecal occult blood test-based colorectal cancer screening sent to the general population at average colorectal cancer risk. (PROSPERO 2020 CRD42020169409). Overall, 34 studies were included. Invitations with an attached, i.e., mailed fecal occult blood test consistently increased test usage by 4–19.7% points, compared to other methods of test provision. Likewise, the introduction of advance notification consistently led to a higher usage rate, with an increase of 3.3–10.8% points. Reminders showed positive but varying effects by method. With an increase of 8.5–15.8% points, letter or email reminders were more effective than reminders by phone call or text message (0.6–6.5% points). Inconsistent results were found for financial incentives ((−8.4)–20% points) and for added or changed invitation material ((−3.5)–11.8% points). With 3.5–24.7% points, the strongest increases in use were achieved by multifaceted invitation, implementing multiple components. Any invitation scheme was superior over no invitation. Advance notification, mailing of fecal occult blood test, and reminders were consistently shown to have major, complementary potential to increase participation in fecal occult blood test-based colorectal cancer screening settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Fecal occult blood tests (FOBTs) detect colorectal cancer (CRC) at high levels of sensitivity and specificity. However, the detection of early-stage cancers is highly important to reduce CRC mortality. We aimed to assess the sensitivity of a large number of different FOBTs according to various tumor characteristics. We observed among all FOBTs consistently lower sensitivities for UICC stage I cancers in comparison to more advanced cancer stages. An even stronger gradient was found according to T status, with substantially lower sensitivities for T1 than for T2–T4 cancers. Furthermore, sensitivities for T1 cancers were even lower than sensitivities for detection of multiple advanced adenomas. Further research should focus on improving the sensitivity of non-invasive tests for detection of UICC stage I and T1 cancers. Background: Fecal immunochemical tests (FITs) are widely used for colorectal cancer (CRC) screening. The detection of early-stage cancer and advanced adenoma (AA), the most important premalignant lesion, is highly relevant to reducing CRC-related deaths. We aimed to assess sensitivity for the detection of CRC and AA stratified by tumor stage; number; size; histology of AA; and by location, age, sex, and body mass index (BMI). Methods: Participants of screening colonoscopy (n = 2043) and newly diagnosed CRC patients (n = 184) provided a stool sample before bowel preparation or CRC surgery. Fecal hemoglobin concentration was determined in parallel by nine different quantitative FITs among 94 CRC patients, 200 AA cases, and 300 participants free of advanced neoplasm. Sensitivities were calculated at original cutoffs and at adjusted cutoffs, yielding 93% specificity among all FITs. Results: At adjusted cutoffs, UICC stage I cancers yielded consistently lower sensitivities (range: 62–68%) compared to stage II–IV cancers (range: 73–89%). An even stronger gradient was observed according to T status, with substantially lower sensitivities for T1 (range: 39–57%) than for T2–T4 cancers (range: 71–100%). Sensitivities for the detection of participants with multiple AAs ranged from 55% to 64% and were by up to 25% points higher than sensitivities for T1 cancers. Conclusions: FITs detect stage I cancers and especially T1 cancers at substantially lower sensitivities than more advanced cancer stages. Participants with multiple AAs were detected with slightly lower sensitivities than stage I cancers and with even higher sensitivities than T1 cancers. Further research should focus on improving the detection of early-stage cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we estimate the number of avoidable deaths attributable to socioeconomic inequalities in cancer survival in Germany. We used data from epidemiological cancer registries. The German Index of Multiple Deprivation (GIMD) 2010 was used to assess deprivation on a municipality level. Results show that summed over the 25 cancer sites, 4100 annual excess deaths (3.0% of all excess deaths) could have been avoided each year in Germany during the period 2013–2016 if relative survival were in all regions comparable with the least deprived regions. Colorectal, oral and pharynx, prostate, and bladder cancer contributed the largest numbers of avoidable excess deaths. We also observed that cancer incidence was generally higher in more deprived areas. Our analyses demonstrate the importance of cancer prevention and of survival improvements in more deprived regions. Many countries have reported survival inequalities due to regional socioeconomic deprivation. To quantify the potential gain from eliminating cancer survival disadvantages associated with area-based deprivation in Germany, we calculated the number of avoidable excess deaths. We used population-based cancer registry data from 11 of 16 German federal states. Patients aged ≥15 years diagnosed with an invasive malignant tumor between 2008 and 2017 were included. Area-based socioeconomic deprivation was assessed using the quintiles of the German Index of Multiple Deprivation (GIMD) 2010 on a municipality level nationwide. Five-year age-standardized relative survival for 25 most common cancer sites and for total cancer were calculated using period analysis. Incidence and number of avoidable excess deaths in Germany in 2013–2016 were estimated. Summed over the 25 cancer sites, 4100 annual excess deaths (3.0% of all excess deaths) could have been avoided each year in Germany during the period 2013–2016 if relative survival were in all regions comparable with the least deprived regions. Colorectal, oral and pharynx, prostate, and bladder cancer contributed the largest numbers of avoidable excess deaths. Our results provide a good basis to estimate the potential of intervention programs for reducing socioeconomic inequalities in cancer burden in Germany. [ABSTRACT FROM AUTHOR]

Simple Summary: Smoking causes the majority of lung cancers. Smoking history is thus used to select individuals among whom screening for lung cancer could be the most beneficial. The aim of our study was to estimate sensitivity and specificity of pre-selection by heavy smoking in individual European countries. Due to differences in smoking histories across the countries and sexes within the countries, the sensitivities were found to be between 33 and 80% for men and between 9 and 79% for women. Corresponding specificities of heavy smoking varied between 48 and 90% (men) and 70 and 99% (women). Our results may inform the design of lung cancer screening programs in European countries and serve as benchmarks for novel alternative or complementary tests for selecting people at high risk for computed tomography-based lung cancer screening. Lung cancer (LC) screening often focuses heavy smokers as a target for screening group. Heavy smoking can thus be regarded as an LC pre-screening test with sensitivities and specificities being different in various populations due to the differences in smoking histories. We derive here expected sensitivities and specificities of various criteria to preselect individuals for LC screening in 27 European countries with diverse smoking prevalences. Sensitivities of various heavy-smoking-based pre-screening criteria were estimated by combining sex-specific proportions of people meeting these criteria in the target population for screening with associations of heavy smoking with LC risk. Expected specificities were approximated by the proportion of individuals not meeting the heavy smoking definition. Estimated sensitivities and specificities varied widely across countries, with sensitivities being generally higher among men (range: 33–80%) than among women (range: 9–79%), and specificities being generally lower among men (range: 48–90%) than among women (range: 70–99%). Major variation in sensitivities and specificities was also seen across different pre-selection criteria for LC screening within individual countries. Our results may inform the design of LC screening programs in European countries and serve as benchmarks for novel alternative or complementary tests for selecting people at high risk for CT-based LC screening. [ABSTRACT FROM AUTHOR]

Background: Breast cancer treatment has changed tremendously over the last decades. In addition, the use of mammography screening for early detection has increased strongly. To evaluate the impact of these developments, long-term trends in incidence, mortality, stage distribution and survival were investigated for Germany and the United States (US). Methods: Using population-based cancer registry data, long-term incidence and mortality trends (1975–2015), shifts in stage distributions (1998–2015), and trends in five-year relative survival (1979–2015) were estimated. Additionally, trends in five-year relative survival after standardization for stage were explored (2004–2015). Results: Age-standardized breast cancer incidence rates were much higher in the US than in Germany in all periods, whereas age-standardized mortality began to lower in the US from the 1990s on. The largest and increasing differences were observed for patients aged 70+ years with a 19% lower incidence but 45% higher mortality in Germany in 2015. For this age group, large differences in stage distributions were observed, with 29% (Germany) compared to 15% (US) stage III and IV patients. Age-standardized five-year relative survival increased strongly between 1979–1983 and 2013–2015 in Germany (+17% units) and the US (+19% units) but was 9% units lower in German patients aged 70+ years in 2013–2015. This difference was entirely explained by differences in stage distributions. Conclusions: Overall, our results are in line with a later uptake and less extensive utilization of mammography screening in Germany. Further studies and efforts are highly needed to further explore and overcome the increased breast cancer mortality among elderly women in Germany. [ABSTRACT FROM AUTHOR]

In the past two decades, an extensive rollout of colorectal cancer (CRC) screening programmes has been initiated in European countries with a large heterogeneity of screening offers. Using data from a population-based cross-sectional survey conducted between 2013 and 2016 in all European Union countries, we analysed the utilisation of faecal tests and colonoscopy among people aged 50–74 years and the factors associated with uptake by type of screening offer. We observed the highest utilisation of either test for countries with fully rolled out organised programmes with faecal tests (ranging from 29.7% in Croatia to 66.7% in the UK) and countries offering both faecal tests and colonoscopy (from 22.7% in Greece to 70.9% in Germany). Utilisation was very low for countries with no programme (from 6.3% in Romania to 30.5% in Norway). Younger age (50–54 years), longer time since last consultation with a doctor and a lifestyle score associated with increased CRC risk were significantly associated with lower test use, a pattern observed across all types of screening offers. Our results suggest that more countries should implement organised programmes with faecal immunochemical tests, in combination with alternative endoscopy offers where resources allow. Furthermore, there is a large potential for increasing screening use in Europe by better reaching the younger eligible individuals, those who have not been to the doctor recently and those at increased risk for CRC. [ABSTRACT FROM AUTHOR]

Objective: Plasma protein biomarkers could be an efficient alternative for population-based screening for early detection of colorectal cancer (CRC). The objective of this study was to evaluate and validate plasma proteins individually and as a signature for early detection of CRC. Methods: In a three-stage design, proteins were measured firstly by liquid chromatography/multiple reaction monitoring-mass spectrometry (LC/MRM-MS) and later by proximity extension assay (PEA) in a discovery set consisting of 96 newly diagnosed CRC cases and 94 controls free of neoplasms at screening colonoscopy. Two algorithms (one for each measurement method) were derived by Lasso regression and.632+ bootstrap based on 11 proteins that were included in both the LC/MRM-MS and PEA measurements. Additionally, another algorithm was constructed from the same eleven biomarkers plus amphireglin, the most promising protein marker in the PEA measurements that had not been available from the LC/MRM-MS measurements. Lastly the three prediction signatures were validated with PEA in independent samples of participants of screening colonoscopy (CRC (n = 56), advanced adenoma (n = 101), and participants free of neoplasm (n = 102)). Results: The same four proteins were included in all three prediction signatures; mannan binding lectin serine protease 1, osteopontin, serum paraoxonase lactonase 3 and transferrin receptor protein 1, and the third prediction signature additionally included amphiregulin. In the independent validation set from a true screening setting, the five-marker blood-based signature including AREG presented areas under the curves of 0.82 (95% CI, 0.74–0.89), 0.86 (95% CI, 0.77–0.92) and 0.76 (95% CI, 0.64–0.86) for all, early and late stages CRC, respectively. Conclusion: Two different measurement methods consistently identified four protein markers and an algorithm additionally including amphiregulin, a marker measured by PEA only, showed promising performance for detecting early stage CRC in an independent validation in a true screening setting. These proteins may be potential candidates for blood-based tests for early detection of CRC. [ABSTRACT FROM AUTHOR]

Despite consistent evidence that comorbidities and functional status (FS) are strong prognostic factors for colorectal cancer (CRC) patients, these important characteristics are not considered in prognostic nomograms. We assessed to what extent incorporating these characteristics into prognostic models enhances prediction of CRC prognosis. CRC patients diagnosed in 2003–2014 who were recruited into a population-based study in Germany and followed over a median time of 4.7 years were randomized into training (n = 1608) and validation sets (n = 1071). In the training set, Cox models with predefined variables (age, sex, stage, tumor location, comorbidity scores, and FS) were used to construct nomograms for relevant survival outcomes. The performance of the nomograms, compared to models without comorbidity and FS, was evaluated in the validation set using concordance index (C-index). The C-indexes of the nomograms for overall and disease-free survival in the validation set were 0.768 and 0.737, which were substantially higher than those of models including tumor stage only (0.707 and 0.701) or models including stage, age, sex, and tumor location (0.749 and 0.718). The nomograms enabled significant risk stratification within all stages including stage IV. Our study suggests that incorporating comorbidities and FS into prognostic nomograms could substantially enhance prediction of CRC prognosis. [ABSTRACT FROM AUTHOR]

DNA methylation profiles within whole-blood samples have been reported to be associated with colorectal cancer (CRC) occurrence and might enable risk stratification for CRC. We systematically reviewed and summarized studies addressing the association of whole-blood DNA methylation markers and risk of developing CRC or its precursors. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 12th November 2018. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, methylation levels of patients in comparison to healthy controls, p-values, and odds ratios of the markers. Overall, 19 studies reporting 102 methylation markers for risk assessment of colorectal neoplasms met our inclusion criteria. The studies mostly used Methylation Specific Polymerase Chain Reaction (MS-PCR) for assessing the methylation status of a defined set of genes. Only two studies applied array-based genome-wide assays to assess the methylation levels. Five studies incorporated panels consisting of 2–10 individual methylation markers to assess their potential for stratifying the risk of developing colorectal neoplasms. However, none of these associations was confirmed in an independent cohort. In conclusion, whole-blood DNA methylation markers may be useful as biomarkers for risk stratification in CRC screening, but reproducible risk prediction algorithms are yet to be established by large scale epigenome-wide studies with thorough validation of results in prospective study cohorts including large screening populations. The possibilities of enhancing predictive power by combining methylation data with polygenetic risk scores and environmental risk factors need to be explored. [ABSTRACT FROM AUTHOR]

Background: Lung cancer (LC) is the leading cause of cancer-related death in Eastern Asia. The prognosis of LC highly depends on tumor stages and early detection could substantially reduce LC mortality. Accumulating evidence suggested that circulating miRNAs in plasma or serum may have applications in early LC detection. We thus conducted a systematic literature review on the diagnostic value of miRNAs markers for LC in East Asian populations. Methods: PubMed and ISI Web of Knowledge were searched to retrieve relevant articles published up to 17 September 2018. Information on study design, population characteristics, investigated miRNAs and diagnostic accuracy (including sensitivity, specificity and area under the curve (AUC)) were independently extracted by two reviewers. Results: Overall, 46 studies that evaluated a total of 88 miRNA markers for LC diagnosis in East Asian populations were identified. Sixteen of the 46 studies have incorporated individual miRNA markers as panels (with 2–20 markers). Three promising miRNA panels with ≥90% sensitivity and ≥90% specificity were discovered, two of which were externally validated. Diagnostic performance of circulating miRNAs in East Asian populations was comparable to previously summarized performance in Western populations. Forty-four miRNAs were reported in both populations. No major differences in diagnostic performance by ethnicity of the same miRNA was observed. Conclusions: Circulating miRNAs or miRNA panels, possibly in combination with other promising molecular markers including epigenetic and genetic markers, may be promising candidates for noninvasive LC early detection. However, large studies with samples collected prospectively in true screening settings are required to validate the promising markers or marker panels. [ABSTRACT FROM AUTHOR]

Fecal immunochemical tests (FITs) for hemoglobin (Hb) are increasingly used for colorectal cancer (CRC) screening. Most FIT manufacturers instruct that fecal samples from multiple parts of one bowel movement should be obtained. Our aim was to compare the FIT diagnostic performance based on fecal samples from just one versus two different sites of one bowel movement. A total of 1141 participants of screening colonoscopy provided two fecal samples from two different sites of a single bowel movement for FIT analyses. There was no statistically significant difference in the diagnostic performance of the FIT when either one or both fecal samples were used for analysis, with area under the curve (AUC) for detecting CRC ranging from 0.94 (95% confidence interval (CI) 0.84–0.99) for one FIT to 0.95 (95%CI 0.86–0.99) for a geometric mean of two FITs. The manufacturers' recommendation of sampling multiple sites of the stool aims to reduce intra-individual Hb variability and improve diagnostic performance. If no such improvement can be achieved, the recommendation for multiple-site sampling might have potential adverse effects on population adherence to FIT-based CRC screening. Our results point to a potential of increasing adherence to FIT screening by simplifying instructions for fecal sampling at no loss of the diagnostic performance. [ABSTRACT FROM AUTHOR]

A variety of fecal immunochemical tests (FITs) are used for colorectal cancer screening. FIT performance could be improved further. It is unclear, whether the combination of different FITs with different analytical characteristics (such as, different antibodies for the detection of fecal hemoglobin) can yield a better diagnostic performance. Fecal samples were obtained from 2042 participants of screening colonoscopy. All participants with advanced neoplasm (AN, colorectal cancer (n = 16) or advanced adenoma (n = 200)) and 300 randomly selected participants without AN were included. Nine quantitative FITs were evaluated simultaneously. Sensitivity and specificity was calculated for single tests (n = 9) and for their pairwise test combinations (n = 36) (requiring either both FITs (P++) or at least one FIT (P+) to be positive for defining a positive test result). Mean age of the participants (n = 516) was 63 (range: 50–79) years and 56% were men. At cutoffs yielding a specificity of 96.7% for single FITs, the median gain in specificity by P++ combination was +1.0%, whereas the median loss in sensitivity for AN was −4.2%. For P+ combination the median gain in sensitivity for AN was +2.8%, at a prize of median loss of −1.0% of specificity. Combinations of different FITs do not yield any relevant gain in diagnostic performance. [ABSTRACT FROM AUTHOR]

Background: Several approaches have been suggested to be useful in the early detection of colorectal neoplasms. Since metabolites are closely related to the phenotype and are available from different human bio-fluids, metabolomics are candidates for non-invasive early detection of colorectal neoplasms. Objectives: We aimed to summarize current knowledge on performance characteristics of metabolomics biomarkers that are potentially applicable in a screening setting for the early detection of colorectal neoplasms. Design: We conducted a systematic literature search in PubMed and Web of Science and searched for biomarkers for the early detection of colorectal neoplasms in easy-to-collect human bio-fluids. Information on study design and performance characteristics for diagnostic accuracy was extracted. Results: Finally, we included 41 studies in our analysis investigating biomarkers in different bio-fluids (blood, urine, and feces). Although single metabolites mostly had limited ability to distinguish people with and without colorectal neoplasms, promising results were reported for metabolite panels, especially amino acid panels in blood samples, as well as nucleosides in urine samples in several studies. However, validation of the results is limited. Conclusions: Panels of metabolites consisting of amino acids in blood and nucleosides in urinary samples might be useful biomarkers for early detection of advanced colorectal neoplasms. However, to make metabolomic biomarkers clinically applicable, future research in larger studies and external validation of the results is required. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer mortality globally. Fecal miRNAs have been suggested to be promising biomarkers for CRC early detection. We aimed to conduct a systematic literature review on the diagnostic performance of fecal miRNA markers for CRC and its precursors. PubMed and Web of Science were searched to retrieve relevant articles published up to 7 December 2021. Information on study design, characteristics of study population, pre-analytics (sample collection, processing, and storage), fecal miRNA extraction and quantification technologies, and diagnostic performance (including sensitivity, specificity, and area under the curve (AUC)) were summarized. Twenty studies reporting on 31 individual miRNAs and 16 miRNA panels (with 2-9 markers) for CRC diagnosis were identified. Substantial heterogeneity existed regarding stool sample collection, processing, storage, and miRNA extraction and normalization. For two individual miRNAs and one miRNA panel, values ≥ 80% were reported for both sensitivity and specificity; however, none of these results were either internally or externally validated. In a study among fecal immunochemical test-positive cases recruited from a true screening setting, better diagnostic performance was identified and internally validated for a combination panel including two miRNAs, fecal hemoglobin level, and patient age and sex, compared with fecal hemoglobin concentration alone. Fecal miRNAs or miRNA panels, possibly in combination with fecal hemoglobin test, may be promising candidates for noninvasive CRC early detection. However, large prospective and well-designed studies in CRC screening cohorts are required to validate promising miRNAs or miRNA panels.

In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model ( p -2df = 1.2 × 10 -3 ). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model ( p -2df = 1.1 × 10 -4 ). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, DAPK2 ( p = 2.19 × 10 -5 ) and ATG5 ( p = 6.28 × 10 -4 ) were associated with the risk of CRC. Mechanistically, the DAPK2 rs11631973G allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with Staphylococcus aureus ( p = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood ( p = 0.0038) and serum levels of en-RAGE ( p = 0.0068). ATG5 rs546456T allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS ( p = 0.0088 and p = 0.0076, respectively), CD14+CD16- cell levels in blood ( p = 0.0068) and serum levels of CCL19 and cortisol ( p = 0.0052 and p = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the DAPK2 and ATG5 loci in the pathogenesis of CRC, likely through the modulation of host immune responses.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.