Correlation between adenoma detection rate in colonoscopy- and fecal immunochemical testing-based colorectal cancer screening programs.

BACKGROUND: The adenoma detection rate (ADR) is the main quality indicator of colonoscopy. The ADR recommended in fecal immunochemical testing (FIT)-based colorectal cancer screening programs is unknown. METHODS: Using the COLONPREV (NCT00906997) study dataset, we performed a post-hoc analysis to determine if there was a correlation between the ADR in primary and work-up colonoscopy, and the equivalent figure to the minimal 20% ADR recommended. Colonoscopy was performed in 5722 individuals: 5059 as primary strategy and 663 after a positive FIT result (OC-Sensor™; cut-off level 15 µg/g of feces). We developed a predictive model based on a multivariable lineal regression analysis including confounding variables. RESULTS: The median ADR was 31% (range, 14%-51%) in the colonoscopy group and 55% (range, 21%-83%) in the FIT group. There was a positive correlation in the ADR between primary and work-up colonoscopy (Pearson's coefficient 0.716; p < 0.001). ADR in the FIT group was independently related to ADR in the colonoscopy group: regression coefficient for colonoscopy ADR, 0.71 (p = 0.009); sex, 0.09 (p = 0.09); age, 0.3 (p = 0.5); and region 0.00 (p = 0.9). The equivalent figure to the 20% ADR was 45% (95% confidence interval, 35%-56%). CONCLUSIONS: ADR in primary and work-up colonoscopy of a FIT-positive result are positively and significantly correlated.

Incidence of advanced neoplasia during surveillance in high- and intermediate-risk groups of the European colorectal cancer screening guidelines.

Background and study aims: The European guidelines for quality assurance in colorectal cancer (CRC) screening have established high-risk (≥ 5 adenomas or an adenoma ≥ 20 mm) and intermediate-risk (3 - 4 adenomas or at least one adenoma 10 - 19 mm in size, or villous histology, or high grade dysplasia) groups with different endoscopic surveillance intervals. The aim of this study was to evaluate the difference in the incidence of advanced neoplasia (advanced adenoma or CRC) between the two risk groups. Patients and methods: This retrospective group study included patients meeting high- or intermediate-risk criteria for adenomas detected in CRC screening programs and the COLONPREV study before European guidelines were adopted in Spain (June 2011) with a 3-year surveillance recommendation according to Spanish guidelines. The primary outcome measure was the incidence of advanced neoplasia in patients undergoing surveillance. The secondary outcome measure was the CRC incidence. We used an adjusted proportional hazards regression model to control confounding variables. Results: The study included 5401 patients (3379 intermediate risk, 2022 high risk). Endoscopic surveillance was performed in 65.5 % of the patients (2.8 ±â€Š1 years). The incidence of advanced neoplasia in the high- and intermediate-risk groups was 16.0 % (59.0 cases/1000 patient-years) and 12.3 % (41.2 cases/1000 patient-years), respectively. The CRC incidence was 0.5 % (1.4 cases/1000 patient-years) and 0.4 % (1 case/1000 patient-years), respectively. The advanced neoplasia and CRC attributable risk to the high risk group was of 3.7 % and 0.1 %, respectively. In the proportional hazards analysis, the risk of advanced neoplasia was greater in the high-risk group (hazard ratio [HR] 1.5, 95 % confidence interval [CI] 1.2 - 1.8), with no significant differences in the CRC incidence (HR 1.6, 95 %CI 0.6 - 3.8). Conclusions: Patients meeting high-risk criteria have a higher incidence of advanced neoplasia during endoscopic surveillance. No differences were found in the CRC incidence at a 3-year surveillance recommendation.

Risk of Advanced Neoplasia in First-Degree Relatives with Colorectal Cancer: A Large Multicenter Cross-Sectional Study.

BACKGROUND: First-degree relatives (FDR) of patients with colorectal cancer have a higher risk of developing colorectal cancer than the general population. For this reason, screening guidelines recommend colonoscopy every 5 or 10 y, starting at the age of 40, depending on whether colorectal cancer in the index-case is diagnosed at <60 or ≥60 y, respectively. However, studies on the risk of neoplastic lesions are inconclusive. The aim of this study was to determine the risk of advanced neoplasia (three or more non-advanced adenomas, advanced adenoma, or invasive cancer) in FDR of patients with colorectal cancer compared to average-risk individuals (i.e., asymptomatic adults 50 to 69 y of age with no family history of colorectal cancer). METHODS AND FINDINGS: This cross-sectional analysis includes data from 8,498 individuals undergoing their first lifetime screening colonoscopy between 2006 and 2012 at six Spanish tertiary hospitals. Of these individuals, 3,015 were defined as asymptomatic FDR of patients with colorectal cancer ("familial-risk group") and 3,038 as asymptomatic with average-risk for colorectal cancer ("average-risk group"). The familial-risk group was stratified as one FDR, with one family member diagnosed with colorectal cancer at ≥60 y (n = 1,884) or at <60 y (n = 831), and as two FDR, with two family members diagnosed with colorectal cancer at any age (n = 300). Multiple logistic regression analysis was used for between-group comparisons after adjusting for potential confounders (age, gender, and center). Compared with the average-risk group, advanced neoplasia was significantly more prevalent in individuals having two FDR with colorectal cancer (odds ratio [OR] 1.90; 95% confidence interval [CI] 1.36-2.66, p < 0.001), but not in those having one FDR with colorectal cancer diagnosed at ≥60 y (OR 1.03; 95% CI 0.83-1.27, p = 0.77) and <60 y (OR 1.19; 95% CI 0.90-1.58, p = 0.20). After the age of 50 y, men developed advanced neoplasia over two times more frequently than women and advanced neoplasia appeared at least ten y earlier. Fewer colonoscopies by 2-fold were required to detect one advanced neoplasia in men than in women. Major limitations of this study were first that although average-risk individuals were consecutively included in a randomized control trial, this was not the case for all individuals in the familial-risk cohort; and second, the difference in age between the average-risk and familial-risk cohorts. CONCLUSIONS: Individuals having two FDR with colorectal cancer showed an increased risk of advanced neoplasia compared to those with average-risk for colorectal cancer. Men had over 2-fold higher risk of advanced neoplasia than women, independent of family history. These data suggest that screening colonoscopy guidelines should be revised in the familial-risk population.

Impact of age- and gender-specific cut-off values for the fecal immunochemical test for hemoglobin in colorectal cancer screening.

BACKGROUND: There is no information on the impact of age and gender on the diagnostic yield of different positivity thresholds for the fecal immunochemical test for hemoglobin (FIT). OBJECTIVES: To evaluate the performance of this test at distinct positivity cut-offs in a population-based colorectal cancer (CRC) screening program. METHODS: CRC detection rate (DR), and analysis of resources were evaluated retrospectively, at different cut-offs of FIT (20, 25, 30, 35 and 40µg Hb/g) respect to a reference value (15µg Hb/g), according to age and gender, in a screening population of 10,611 participants of the ColonPrev study (Quintero. NEJM 2013). RESULTS: At the reference cut-off value, 36 CRC and 252 advanced adenomas (AA) were diagnosed. Increasing the cut-off in women ≤60 years decreases colonoscopies performed by 44.5% without modifying the CRC (DR). Same CRC DR was observed in men ≤60 years and women >60 years increasing cut-off at 25-30µg Hb/g. In men >60 years, all increases in the cut-off affected the CRC DR, especially when the cut-off was increased from 35 to 40µg Hb/g (CRC miss rate 25%). CONCLUSIONS: To improve the performance of FIT in CRC screening programs, FIT cut-offs could be individualized by age and gender.

Participation and detection rates by age and sex for colonoscopy versus fecal immunochemical testing in colorectal cancer screening.

PURPOSE: To compare two strategies for colorectal cancer screening: one-time colonoscopy versus fecal immunochemical testing (FIT) (and colonoscopy for positive) every 2 years, in order to determine which strategy provides the highest participation and detection rates in groups of sex and age. METHODS: This analysis was performed with data from the first screening round within the COLONPREV study, a population-based, multicenter, nationwide trial carried out in Spain. Several logistic regression models were applied to identify the influence of the screening test on participation rates and detection of proximal and distal neoplasms, as well to identify the influence of age and sex: women aged 50-59 years, women aged 60-69 years, men aged 50-59 years, and men aged 60-69 years. RESULTS: Participation was higher in women than in men, especially among women aged 50-59 years (25.91 % for colonoscopy and 35.81 % for FIT). Crossover from colonoscopy to FIT was higher among women than men, especially among those aged 60-69 years (30.37 %). In general, detection of any neoplasm and advanced adenoma was higher with colonoscopy than with FIT, but no significant differences were found between the two strategies for colorectal cancer detection. Detection of advanced adenoma in both arms was lower in women [specifically in women aged 50-59 years (OR 0.31; 95 % CI 0.25-0.38) than in men aged 60-69 years]. Women aged 50-59 years in the colonoscopy arm had a higher probability of detection of advanced adenoma (OR 4.49; 95 % CI 3.18-6.35), as well as of detection of neoplasms in proximal and distal locations (proximal OR 19.34; 95 % CI 12.07-31.00; distal OR 11.04; 95 % CI 8.13-15.01) than women of the same age in the FIT arm. These differences were also observed in the remaining groups but to a lesser extent. CONCLUSION: Women were more likely to participate in a FIT-based strategy, especially those aged 50-59 years. The likelihood of detection of any neoplasm was higher in the colonoscopy arm for all the population groups studied, especially in women aged 50-59 years. Distinct population groups should be informed of the benefits of each screening strategy so that they may take informed decisions.

Rate of detection of advanced neoplasms in proximal colon by simulated sigmoidoscopy vs fecal immunochemical tests.

BACKGROUND & AIMS: We compared the ability of biennial fecal immunochemical testing (FIT) and one-time sigmoidoscopy to detect colon side-specific advanced neoplasms in a population-based, multicenter, nationwide, randomized controlled trial. METHODS: We identified asymptomatic men and women, 50-69 years old, through community health registries and randomly assigned them to groups that received a single colonoscopy examination or biennial FIT. Sigmoidoscopy yield was simulated from results obtained from the colonoscopy group, according to the criteria proposed in the UK Flexible Sigmoidoscopy Trial for colonoscopy referral. Patients who underwent FIT and were found to have ≥75 ng hemoglobin/mL were referred for colonoscopy. Data were analyzed from 5059 subjects in the colonoscopy group and 10,507 in the FIT group. The main outcome was rate of detection of any advanced neoplasm proximal to the splenic flexure. RESULTS: Advanced neoplasms were detected in 317 subjects (6.3%) in the sigmoidoscopy simulation group compared with 288 (2.7%) in the FIT group (odds ratio for sigmoidoscopy, 2.29; 95% confidence interval, 1.93-2.70; P = .0001). Sigmoidoscopy also detected advanced distal neoplasia in a higher percentage of patients than FIT (odds ratio, 2.61; 95% confidence interval, 2.20-3.10; P = .0001). The methods did not differ significantly in identifying patients with advanced proximal neoplasms (odds ratio, 1.17; 95% confidence interval, 0.78-1.76; P = .44). This was probably due to the lower performance of both strategies in detecting patients with proximal lesions (sigmoidoscopy detected these in 19.1% of patients and FIT in 14.9% of patients) vs distal ones (sigmoidoscopy detected these in 86.8% of patients and FIT in 33.5% of patients). Sigmoidoscopy, but not FIT, detected proximal lesions in lower percentages of women (especially those 50-59 years old) than men. CONCLUSIONS: Sigmoidoscopy and FIT have similar limitations in detecting advanced proximal neoplasms, which depend on patients' characteristics; sigmoidoscopy underperforms for women 50-59 years old. Screening strategies should be designed on the basis of target population to increase effectiveness and cost-effectiveness. ClinicalTrials.gov number: NCT00906997.

Risk of advanced proximal neoplasms according to distal colorectal findings: comparison of sigmoidoscopy-based strategies.

BACKGROUND: Screening for colorectal cancer with sigmoidoscopy benefits from the fact that distal findings predict the risk of advanced proximal neoplasms (APNs). This study was aimed at comparing the existing strategies of postsigmoidoscopy referral to colonoscopy in terms of accuracy and resources needed. METHODS: Asymptomatic individuals aged 50-69 years were eligible for a randomized controlled trial designed to compare colonoscopy and fecal immunochemical test. Sigmoidoscopy yield was estimated from results obtained in the colonoscopy arm according to three sets of criteria of colonoscopy referral (from those proposed in the UK Flexible Sigmoidoscopy, Screening for COlon REctum [SCORE], and Norwegian Colorectal Cancer Prevention [NORCCAP] trials). Advanced neoplasm detection rate, sensitivity, specificity, and number of individuals needed to refer for colonoscopy to detect one APN were calculated. Logistic regression analysis was performed to identify distal findings associated with APN. All statistical tests were two-sided. RESULTS: APN was found in 255 of 5059 (5.0%) individuals. Fulfillment of UK (6.2%), SCORE (12.0%), and NORCCAP (17.9%) criteria varied statistically significantly (P < .001). The NORCCAP strategy obtained the highest sensitivity for APN detection (36.9%), and the UK approach reached the highest specificity (94.6%). The number of individuals needed to refer for colonoscopy to detect one APN was 6 (95% confidence interval [CI] = 4 to 7), 8 (95% CI = 6 to 9), and 10 (95% CI = 8 to 12) when the UK, SCORE, and NORCCAP criteria were used, respectively. The logistic regression analysis identified distal adenoma ≥10 mm (odds ratio = 3.77; 95% CI = 2.52 to 5.65) as the strongest independent predictor of APN. CONCLUSIONS: Whereas the NORCCAP criteria achieved the highest sensitivity for APN detection, the UK recommendations benefited from the lowest number of individuals needed to refer for colonoscopy.

Genetic susceptibility variants associated with colorectal cancer prognosis.

Colorectal cancer (CRC) is the second leading cause of cancer-related death among men and women in Western countries. Once a tumour develops, a differentiated prognosis could be determined by lifestyle habits or inherited and somatic genetic factors. Finding such prognostic factors will be helpful in order to identify cases with a shorter survival or at a higher risk of recurrence that may benefit from more intensive treatment and follow-up surveillance. Sixteen CRC genetic susceptibility variants were directly genotyped in a cohort of 1235 CRC patients recruited by the EPICOLON Spanish consortium. Univariate Cox and multivariate regression analyses were performed taking as primary outcomes overall survival (OS), disease-free survival and recurrence-free interval. Genetic variants rs9929218 at 16q22.1 and rs10795668 at 10p14 may have an effect on OS. The G allele of rs9929218 was linked with a better OS [GG genotype, genotypic model: hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.45-0.93, P = 0.0179; GG/GA genotypes, dominant model: HR = 0.66, 95% CI 0.47-0.94, P = 0.0202]. Likewise, the G allele of rs10795668 was associated with better clinical outcome (GG genotype, genotypic model: HR = 0.73, 95% CI 0.53-1.01, P = 0.0570; GA genotype, genotypic model: HR = 0.66, 95% CI 0.47-0.92, P = 0.0137; GG/GA genotypes, dominant model: HR = 0.68, 95% CI 0.50-0.94, P = 0.0194). In conclusion, CRC susceptibility variants rs9929218 and rs10795668 may exert some influence in modulating patient's survival and they deserve to be further tested in additional CRC cohorts in order to confirm their potential as prognosis or predictive biomarkers.

Relationship of colonoscopy-detected serrated polyps with synchronous advanced neoplasia in average-risk individuals.

BACKGROUND: Serrated cancers account for 10% to 20% of all colorectal cancers (CRC) and more than 30% of interval cancers. The presence of proximal serrated polyps and large (≥10 mm) serrated polyps (LSP) has been correlated with colorectal neoplasia. OBJECTIVE: To evaluate the prevalence of serrated polyps and their association with synchronous advanced neoplasia in a cohort of average-risk population and to assess the efficacy of one-time colonoscopy and a biennial fecal immunochemical test for reducing CRC-related mortality. This study focused on the sample of 5059 individuals belonging to the colonoscopy arm. DESIGN: Multicenter, randomized, controlled trial. SETTING: The ColonPrev study, a population-based, multicenter, nationwide, randomized, controlled trial. PATIENTS: A total of 5059 asymptomatic men and women aged 50 to 69 years. INTERVENTION: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Prevalence of serrated polyps and their association with synchronous advanced neoplasia. RESULTS: Advanced neoplasia was detected in 520 individuals (10.3%) (CRC was detected in 27 [0.5%] and advanced adenomas in 493 [9.7%]). Serrated polyps were found in 1054 individuals (20.8%). A total of 329 individuals (6.5%) had proximal serrated polyps, and 90 (1.8%) had LSPs. Proximal serrated polyps or LSPs were associated with male sex (odds ratio [OR] 2.08, 95% confidence interval [CI], 1.76-4.45 and OR 1.65, 95% CI, 1.31-2.07, respectively). Also, LSPs were associated with advanced neoplasia (OR 2.49, 95% CI, 1.47-4.198), regardless of their proximal (OR 4.15, 95% CI, 1.69-10.15) or distal (OR 2.61, 95% CI, 1.48-4.58) locations. When we analyzed subtypes of serrated polyps, proximal hyperplasic polyps were related to advanced neoplasia (OR 1.61, 95% CI, 1.13-2.28), although no correlation with the location of the advanced neoplasia was observed. LIMITATIONS: Pathology criteria for the diagnosis of serrated polyps were not centrally reviewed. The morphology of the hyperplasic polyps (protruded or flat) was not recorded. Finally, because of the characteristics of a population-based study carried out in average-risk patients, the proportion of patients with CRC was relatively small. CONCLUSION: LSPs, but not proximal serrated polyps, are associated with the presence of synchronous advanced neoplasia. Further studies are needed to determine the risk of proximal hyperplastic polyps.

[The Alliance for the Prevention of Colorectal Cancer in Spain. A civil commitment to society]. / Alianza para la Prevención del Cáncer de Colon en España: un compromiso cívico con la sociedad.

Colorectal cancer (CRC) is the most common malignant tumor in Spain, when men and women are considered together, and the second leading cause of cancer death. Every week in Spain over 500 cases of CRC are diagnosed, and nearly 260 people die from the disease. Epidemiologic estimations for the coming years show a significant increase in the number of annual cases. CRC is a perfectly preventable tumor and can be cured in 90% of cases if detected in the early stages. Population-based screening programs have been shown to reduce the incidence of CRC and mortality from the disease. Unless early detection programs are established in Spain, it is estimated that in the coming years, 1 out of 20 men and 1 out of 30 women will develop CRC before the age of 75. The Alliance for the Prevention of Colorectal Cancer in Spain is an independent and non-profit organization created in 2008 that integrates patients' associations, altruistic non-governmental organizations and scientific societies. Its main objective is to raise awareness and disseminate information on the social and healthcare importance of CRC in Spain and to promote screening measures, early detection and prevention programs. Health professionals, scientific societies, healthcare institutions and civil society should be sensitized to this highly important health problem that requires the participation of all sectors of society. The early detection of CRC is an issue that affects the whole of society and therefore it is imperative for all sectors to work together.

Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening.

BACKGROUND: Colonoscopy and fecal immunochemical testing (FIT) are accepted strategies for colorectal-cancer screening in the average-risk population. METHODS: In this randomized, controlled trial involving asymptomatic adults 50 to 69 years of age, we compared one-time colonoscopy in 26,703 subjects with FIT every 2 years in 26,599 subjects. The primary outcome was the rate of death from colorectal cancer at 10 years. This interim report describes rates of participation, diagnostic findings, and occurrence of major complications at completion of the baseline screening. Study outcomes were analyzed in both intention-to-screen and as-screened populations. RESULTS: The rate of participation was higher in the FIT group than in the colonoscopy group (34.2% vs. 24.6%, P<0.001). Colorectal cancer was found in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group (odds ratio, 0.99; 95% confidence interval [CI], 0.61 to 1.64; P=0.99). Advanced adenomas were detected in 514 subjects (1.9%) in the colonoscopy group and 231 subjects (0.9%) in the FIT group (odds ratio, 2.30; 95% CI, 1.97 to 2.69; P<0.001), and nonadvanced adenomas were detected in 1109 subjects (4.2%) in the colonoscopy group and 119 subjects (0.4%) in the FIT group (odds ratio, 9.80; 95% CI, 8.10 to 11.85; P<0.001). CONCLUSIONS: Subjects in the FIT group were more likely to participate in screening than were those in the colonoscopy group. On the baseline screening examination, the numbers of subjects in whom colorectal cancer was detected were similar in the two study groups, but more adenomas were identified in the colonoscopy group. (Funded by Instituto de Salud Carlos III and others; ClinicalTrials.gov number, NCT00906997.).

Simplifying the detection of MUTYH mutations by high resolution melting analysis.

BACKGROUND: MUTYH-associated polyposis (MAP) is a disorder caused by bi-allelic germline MUTYH mutation, characterized by multiple colorectal adenomas. In order to identify mutations in MUTYH gene we applied High Resolution Melting (HRM) genotyping. HRM analysis is extensively employed as a scanning method for the detection of heterozygous mutations. Therefore, we applied HRM to show effectiveness in detecting homozygous mutations for these clinically important and frequent patients. METHODS: In this study, we analyzed phenotype and genotype data from 82 patients, with multiple (> or = 10) synchronous (19/82) or metachronous (63/82) adenomas and negative APC study (except one case). Analysis was performed by HRM-PCR and direct sequencing, in order to identify mutations in MUTYH exons 7, 12 and 13, where the most prevalent mutations are located. In monoallelic mutation carriers, we evaluated entire MUTYH gene in search of another possible alteration. HRM-PCR was performed with strict conditions in several rounds: the first one to discriminate the heteroduplex patterns and homoduplex patterns and the next ones, in order to refine and confirm parameters. The genotypes obtained were correlated to phenotypic features (number of adenomas (synchronous or metachronous), colorectal cancer (CRC) and family history). RESULTS: MUTYH germline mutations were found in 15.8% (13/82) of patients. The hot spots, Y179C (exon 7) and G396D (exon 13), were readily identified and other mutations were also detected. Each mutation had a reproducible melting profile by HRM, both heterozygous mutations and homozygous mutations. In our study of 82 patients, biallelic mutation is associated with being a carrier of >/=10 synchronous polyps (p = 0.05) and there is no association between biallelic mutation and CRC (p = 0.39) nor family history (p = 0.63). G338H non-pathogenic polymorphism (exon 12) was found in 23.1% (19/82) of patients. In all cases there was concordance between HRM (first and subsequent rounds) and sequencing data. CONCLUSIONS: Here, we describe a screening method, HRM, for the detection of both heterozygous and homozygous mutations in the gene encoding MUTYH in selected samples of patients with phenotype of MAP. We refine the capabilities of HRM-PCR and apply it to a gene not yet analyzed by this tool. As clinical decisions will increasingly rely on molecular medicine, the power of identifying germline mutations must be continuously evaluated and improved.

Susceptibility genetic variants associated with colorectal cancer risk correlate with cancer phenotype.

BACKGROUND & AIMS: Ten common low-penetrant genetic variants have been consistently associated with colorectal cancer (CRC) risk; little is known about the correlation between these variants and CRC phenotype. Characterization of such a correlation would improve CRC management and prevention programs. We assessed the association between these genetic variants and CRC phenotype in patients and modeled pairwise combinations to detect epistasis. METHODS: The validation population corresponded to a prospective, multicenter, population-based cohort (EPICOLON I) of 1096 patients with newly diagnosed CRC. The replication set was an independent, prospective, multicenter Spanish cohort (EPICOLON II) of 895 patients with newly diagnosed CRC. For individual single nucleotide polymorphism (SNP) association analyses, a multivariate method using logistic regression was applied in EPICOLON I and subsequently prospectively validated in EPICOLON II. Interactions between SNPs were assessed using the likelihood ratio test. RESULTS: Validated results confirmed that the C allele on 8q23.3 (rs16892766) was significantly associated with advanced-stage tumors (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.15-1.90; P value = 4.9 x 10(-3)). The G allele on 8q24.21 (rs6983267) was more common in patients with a familial history of CRC (OR, 2.02; 95% CI, 1.35-3.03; P value = 3.9 x 10(-4)). The combination of rs6983267 on 8q24.21 and rs9929218 on 16q22.2 was associated with a history of colorectal adenoma (carriers of GG and AA, respectively; OR, 2.28; 95% CI, 1.32-3.93; P = 5.0 x 10(-4)). CONCLUSIONS: CRC susceptibility variants at 8q23.3, 8q24.21, and 16q22.2 appear to be associated with cancer phenotype. These findings might be used to develop screening and surveillance strategies.

Clinical performance of original and revised Bethesda guidelines for the identification of MSH2/MLH1 gene carriers in patients with newly diagnosed colorectal cancer: proposal of a new and simpler set of recommendations.

UNLABELLED: Identification of individuals who should undergo hereditary nonpolyposis colorectal cancer (HNPCC) genetic testing is a critical and difficult issue. For this purpose, the National Cancer Institute outlined a set of recommendations, the Bethesda guidelines, which have recently been revised. OBJECTIVE: To compare the clinical performance of original and revised Bethesda guidelines for the detection of MSH2/MLH1 gene carriers in patients with colorectal cancer. METHODS: A total of 1,222 patients with newly diagnosed colorectal cancer were included in the EPICOLON study, a prospective, multicenter, nationwide epidemiology survey aimed at establishing the incidence of HNPCC in Spain (JAMA 2005; 293:1986-1994). Performance characteristics of the original and revised Bethesda guidelines were assessed with respect to the presence of MSH2/MLH1 germline mutations. Logistic regression analysis was performed to establish the most effective strategy. RESULTS: Original or revised Bethesda guidelines were equivalent strategies in terms of sensitivity (100%vs 100%; ns), specificity (98.1%vs 97.9%; ns), and overall accuracy (98.1%vs 97.9%; ns), as well as positive (25.8%vs 24.2%) and negative predictive values (100%vs 100%). The most discriminating individual variables were criteria number 1 (i.e., fulfillment of the Amsterdam criteria; RR = 34.14; 95% CI = 6.85-170.16; p < 0.001) and number 2 (i.e., individuals with two HNPCC-related neoplasms; RR = 35.63; 95% CI = 4.83-262.6; p < 0.001) of the original guidelines, and criterion number 1 of the revised guidelines (i.e., colorectal cancer diagnosed under 50 yr of age; RR = 29.34; 95% CI = 3.81-225.96; p= 0.001). The aggregation of these three criteria was equivalent to both Bethesda guidelines in terms of sensitivity (100%) and negative predictive value (100%), but superior to the revised criteria regarding specificity (98.5%; p < 0.05), overall accuracy (98.5%; p < 0.05), and positive predictive value (30.8%). CONCLUSIONS: Original and revised Bethesda guidelines are equivalent, highly effective criteria for the identification of MSH2/MLH1 gene mutation carriers in patients with newly diagnosed colorectal cancer. A new set of recommendations, based on a combination of some of their individual criteria, may provide additional advantages in terms of effectiveness.