Revised Bethesda Guidelines Research Articles

TUMOUR PATHOLOGY PREDICTS MICROSATELLITE INSTABILITY IN A POPULATION-BASED SERIES OF COLORECTAL CANCER CASES

Background: Lynch Syndrome is an autosomal dominant trait that accounts forapproximately 3% of all cases of colorectal cancer (CRC). It is caused by mutations in DNA mismatch repair (MMR) genes, most commonly MLH1 or MSH2. These MMR defects cause high levels of microsatellite instability (MSI-H) in the tumours. MSI testing of all CRCs to identify potential Lynch Syndrome cases is not practical, so the Bethesda Guidelines, which use clinical and pathological features, were created to identify those tumours most likely to be MSI-H^1. In 2007 Jenkins et. al. created MsPath, a tool based on the pathological features described in the rarely used 3^rd Bethesda criterion, to improve prediction of MSI-H tumours among CRC cases diagnosed before age 60 years^2. Methods: We collected a population-based cohort of 716 CRC cases diagnosed before age 75 years in Newfoundland. For each of these cases we collected family history, performed MSI analysis, and scored a number of pathological features for the purpose of evaluating the accuracy of the Bethesda Criteria and MsPath at predicting MSI-H tumours. Results: Our work validates the MsPath tool in the Newfoundland population for the same age group used to create the tool. We found it identified MSI-H cases with a sensitivity of 95% and specificity of 35% in our population of CRCcases diagnosed before age 60 years (n=290). We also tested this tool on our older population of CRCcases, diagnosed at ages 60 to 74 years (n=426). We found it to be at least as predictive in this population,with a sensitivity of 95% and a specificity of 42%. We then used our entire cohort (N=716) to compare MsPath with the other Bethesda criteria.Bethesda criteria 1, 2, 4 and 5 together predicted MSI-H cases with a sensitivity of 67% and a specificity of 51%. MsPath was better at identifying these cases, with a sensitivity of 95% and a specificity of 39%. Conclusions: We conclude that MsPath can be extended to include patients diagnosed with CRC before age 75 years. As well, we have found that MsPath is a better predictive tool than the Revised Bethesda Guidelines for identifying MSI-H cases within a population-based setting of colorectal cancer.

A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting

Background and aims:In Lynch syndrome, the clinical phenotype in MSH6 mutation families differs from that in MLH1 and MSH2 families. Therefore, MSH6 mutation families are less likely to fulfil diagnostic...

Clinical value of screening hereditary nonpolyposis colorectal cancer in China with protocol recommended by NCCN guidelines

To investigate the effect of the protocol recommended by NCCN-2007 on the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) in China. NCCN protocol consists of identifying HNPCC characteristics according to the revised Bethesda Guidelines,genetic counseling with immunohistochemistry and finally genetic testing. Four hundred and nineteen patients diagnosed as colorectal cancer from January 2002 to February 2006 were selected. The hMLH1 and hMSH2 immunostaining were implemented for 90 patients who fulfilled the revised Bethesda Guidelines, in whom 8 patients fulfilling the Amsterdam II (Criteria were classified as group A and the other 82 patients as group B. The frozen tissues were collected from patients who showed loss of hMLH1 or hMSH2 protein expression, then RNA was extracted, and RT-PCR and cDNA sequencing were adopted to detect the germline mutations of hMLH1 and hMSH2. Tumor tissues from 18 patients showed loss of hMLH1 or hMSH2 protein expression (5 patients in group A and 13 in group B). Finally, 21 patients(8 in group A and 13 in group B showed loss expression of MMR protein) were diagnosed as HNPCC, including 2 cases of hMLH1 and 1 case of hMSH2 mutations. These 3 cases with cDNA mutations did not fulfill the Amsterdam II( Criteria, and were finally diagnosed as HNPCC. The protocol recommended by NCCN-2007 offers a useful approach to identify HNPCC patients,and reduces the possibility of missed diagnosis of HNPCC.

Comparison of predictive models, clinical criteria and molecular tumour screening for the identification of patients with Lynch syndrome in a population-based cohort of colorectal cancer patients

Background:Several models have recently been developed to predict mismatch repair (MMR) gene mutations. Their comparative performance with clinical criteria or universal molecular screening in a population based colorectal cancer (CRC)...

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.

Proximal colon cancer in patients aged 51–60 years of age should be tested for microsatellites instability. A comment on the Revised Bethesda Guidelines

The Bethesda guidelines suggest to perform microsatellite instability (MSI) test in early onset rectal cancer and not in patients>50 years with proximal colon cancer. The aim of the study was to evaluate whether the risk of high MSI (MSI-H) is greater in proximal colon cancer of patients 51-60 years old than in early-onset rectal cancer. Consecutive colorectal cancer (CRC) patients were evaluated. Tumor location, cancer family history, MSI status and histology were recorded. Mutations in MLH1/MSH2 were investigated in MSI-H tumors. Patients were subdivided into groups: group A, proximal colon cancer patients 51-60 years old and groups B, C and D, patients<or=50 years old, with rectal cancer, proximal and distal colon cancer, respectively. Out of 409 CRC patients evaluated, 48 (12%) showed tumors with MSI-H. No MSI-H tumors were found in distal and rectal tumors of patients at sixth decade of life. Group A included 27 patients, eight (29.7%) MSI-H cancers, four missense mutations in MLH1/MSH2; groups B, C and D included 26, 11 and 11 patients with two (7.7%), two (18%) and two (18%) MSI-H cancers, respectively. One missense mutation on MSH2 in group B, one pathogenetic mutation on MSH1 in group C and one pathogenetic mutation on MSH2 in group D were found. Tumors of group A showed an increased probability to have MSI-H if compared to those of group B (OD=4.907, p=0.043). The Bethesda criteria should be broadened to include patients 51-60 years old with proximal colon cancer.

Tumor histology helps to identify Lynch syndrome among colorectal cancer patients

To determine the value of histology in identifying Lynch syndrome among those patients with early onset of colorectal cancer (CRC). Demographic, clinical and cancer history data from patients diagnosed with CRC before 60 years of age, and treated at our institution between 1997 and 2005, were collected from medical records and direct interview. Their tumors were assessed to identify histological features suggestive of high frequency microsatellite instability (MSI-H): tumor infiltrating lymphocytes, Crohn's like inflammatory reaction, mucinous, signet ring cells, medullary growth pattern and then, tested for microsatellite instability (MSI) and MLH1/ MSH2 protein expression. Sixty-five patients were included in the study. The mean age at diagnosis was 48 +/- 9.9 years. Overall, 28 (43%) patients, including 13 of 35 diagnosed between ages 50 and 60, had tumor demonstrating one or more histological features suggestive of MSI-H. These patients were younger (45 vs. 50 years, P = 0.02) and more commonly had family history of Lynch syndrome-related cancers (36 vs. 19%), though the latter feature did not reach statistical significance (P = 0.07). Eleven of 25 tumors with MSI-H histology, but only 1 of 29 tumors without special histological features were found to be MSI-H (P < 0.0001). Histology had a positive predictive value of 44% and a negative predictive value of 97% for identifying MSI-H tumors. Limiting MSI analysis only to those tumors with suggestive histology would have reduced the need for testing by nearly 60% of all tumors from patients that met the revised Bethesda guidelines.

Detection of mismatch repair gene germline mutation carrier among Chinese population with colorectal cancer

BackgroundHereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome. The National Cancer Institute (NCI) has recommended the Revised Bethesda guidelines for screening HNPCC. There has been a great deal of research on the value of these tests in other countries. However, literature about the Chinese population is scarce. Our objective is to detect and study microsatellite instability (MSI) and mismatch repair (MMR) gene germline mutation carriers among a Chinese population with colorectal cancer.MethodsIn 146 prospectively recruited consecutive patients with clinically proven colorectal cancer, MSI carriers were identified by analysis of tumor tissue using multiplex fluorescence polymerase chain reaction (PCR) using the NCI recommended panel and classified into microsatellite instability-low (MSI-L), microsatellite instability-high (MSI-H) and microsatellite stable (MSS) groups. Immunohistochemical staining for MSH2, MSH6 and MLH1 on tissue microarrays (TMAs) was performed, and methylation of the MLH1 promoter was analyzed by quantitative methylation specific PCR (MSP). Germline mutation analysis of blood samples was performed for MSH2, MSH6 and MLH1 genes.ResultsThirty-four out of the 146 colorectal cancers (CRCs, 23.2%) were MSI, including 19 MSI-H CRCs and 15 MSI-L CRCS. Negative staining for MSH2 was found in 8 CRCs, negative staining for MSH6 was found in 6 CRCs. One MSI-H CRC was negative for both MSH6 and MSH2. Seventeen CRCs stained negatively for MLH1. MLH1 promoter methylation was determined in 34 MSI CRCs. Hypermethylation of the MLH1 promoter occurred in 14 (73.7%) out of 19 MSI-H CRCs and 5 (33.3%) out of 15 MSI-L CRCs. Among the 34 MSI carriers and one MSS CRC with MLH1 negative staining, 8 had a MMR gene germline mutation, which accounted for 23.5% of all MSI colorectal cancers and 5.5% of all the colorectal cancers. Five patients harbored MSH2 germline mutations, and three patients harbored MSH6 germline mutations. None of the patients had an MLH1 mutation. Mutations were commonly located in exon 7 and 12 of MSH2 and exon 5 of MSH6. Right colonic lesions and mucinous carcinoma were not common in MSI carriers.ConclusionOur data may imply that the characteristics of HNPCC in the Chinese population are probably different from those of Western countries. Application of NCI recommended criteria may not be effective enough to identify Chinese HNPCC families. Further studies are necessary to echo or refute our results so as to make the NCI recommendation more universally applicable.

A Prospective, Multicenter, Population-Based Study of BRAF Mutational Analysis for Lynch Syndrome Screening

Mismatch repair (MMR) deficiencies are the hallmark of tumors arising in Lynch syndrome, however, in approximately 15% of sporadic colorectal cancers (CRC) these deficiencies most often are associated with somatic methylation of the MMR gene MLH1. Recently, an oncogenic mutation in the BRAF gene has been involved in sporadic CRC showing MMR deficiencies as a result of MLH1 promoter methylation. The aim of this study was to evaluate the contribution of BRAF V600E mutation analysis in the identification of MSH2/MLH1 gene mutation carriers in newly diagnosed CRC patients. BRAF V600E mutation was analyzed in CRC patients with MMR deficiencies (microsatellite instability and/or lack of MLH1/MSH2 protein expression) in the EPICOLON population-based study. The effectiveness and efficiency of different strategies were evaluated with respect to the presence of MSH2/MLH1 germline mutations. MMR deficiencies were detected in 119 of the 1222 CRC patients with tumors showing either microsatellite instability (n = 111) or loss of protein expression (n = 81). BRAF mutation was detected in 22 (18.5%) of the patients. None of the patients with unambiguous germline mutation had BRAF mutation. Regardless of the strategy used to identify MSH2/MLH1 gene carriers, the introduction of BRAF analysis in these patients slightly improves their effectiveness. The introduction of BRAF mutation analysis as a step before germline genetic testing in patients with MMR deficiencies achieved a significant reduction in costs per mutation detected. Detection of BRAF V600E mutation could simplify and improve the cost effectiveness of genetic testing for hereditary nonpolyposis colorectal cancer, especially in patients whose family history is incomplete or unknown.

How Should Women With Early-Onset Endometrial Cancer Be Evaluated for Lynch Syndrome?

How Should Women With Early-Onset Endometrial Cancer Be Evaluated for Lynch Syndrome?

Familial Colorectal Cancer Syndrome X

In recent decades there have been significant advances in our understanding of the genes that underlie hereditary susceptibility to colorectal cancer (CRC). In 2007 it is well established that mutations in DNA repair genes (MLH1, MSH2, MSH6, MYH) and Wnt pathway signal transduction inhibitors (APC) underlie a significant percentage of hereditary CRC susceptibility. However, it also is clear that the known CRC susceptibility genes do not explain fully the inherited risk seen even in families meeting the revised Bethesda guidelines. Furthermore, the optimal medical management of these syndromes is still being defined. What underlies CRC susceptibility in these highly unusual families that do not have identifiable mutations in the known genes, often referred to as syndrome X? This review addresses this important question that is relevant to our current understanding of the management of individuals with hereditary predisposition to CRC.

Validation of the PREMM1,2 model for the prediction of MLH1/MSH2 germline mutation carriers in a population- based cohort of colorectal cancer (CRC) patients

10545 Background: PREMM1,2 is a predictive model for estimating the likelihood of finding a mutation in the MLH1 and MSH2 genes developed in a population at risk of Lynch syndrome (Balmaña et al. JAMA 2006). The EPICOLON cohort is a Spanish population-based series of 1222 patients with CRC (Piñol et al. JAMA 2005). Methods: All 1222 individuals underwent microsatellite instability (MSI) and immunohistochemistry (IHC) analysis for MLH1/MSH2. Patients whose tumours exhibited MSI or altered IHC underwent MLH1/MSH2 analysis (n=91). Sensitivity (Se), specificity, positive predictive value (PPV), and the areas under the receiver operating characteristics curves (AUC) for the PREMM1,2 model were calculated and compared with the Edinburgh model (Barnetson et al. NEJM 2006) and the Revised Bethesda guidelines (RBG). Results: Three-hundred and ninety six individuals (32%) had a PREMM1,2 score =5%, 287 (23%) fulfilled the RBG, and 75 (6%) had a Barnetson score =5%. A PREMM1,2 score =5% and the RBG identified all carriers with deleterious mutations (n=8, Se=100%), while a Barnetson score =5% missed 2 mutation carriers (Se= 75%). For PREMM1,2 and Barnetson scores =5% and fulfilment of the RBG, specificities were 68%, 94%, and 77%, respectively; and PPV were 2%, 8%, and 2.8%, respectively. The AUC was 0.93 (95% CI: 0.86–0.99) for the PREMM1,2 model and 0.86 (95% CI: 0.66–1.04) for the Barnetson model. The predictions of carrying a mutation stratified into five groups based on PREMM1,2 scores (&lt;5%, 5–9%, 10–19%, 20–39%, =40%) correlated reasonably with the presence of mutations (0%, 1%, 1%, 13%, and 22%, respectively). Conclusions: In a population of CRC patients, the PREMM1,2 model identifies all mutation carriers of MSH2 and MLH1 using a cutoff of =5%. In addition, it provides quantification of risk that is useful to decide the strategy used for molecular evaluation and risk counselling of patients. No significant financial relationships to disclose.

Screening the hereditary nonpolyposis colorectal cancer by revised Bethesda guideline: a cohort study of 110 cases

To study the value of screening hereditary nonpolyposis colorectal cancer (HNPCC) by the revised Bethesda guideline and the rate of HNPCC in colorectal cancer (CRC). Tumor tissues and normal colorectal mucous membrane tissues were collected from 110 successive cases with CRC, 66 males and 42 females, aged 60.8 (26 - 94). Fluorescence multiplex polymerase chain reaction was used to detect the microsatellite instability (MSI). The peripheral blood samples were collected from the patients with MSI, genomic DNA was extracted, and PCR and DNA sequencing were used to detect the germline mutations of hMSH2, hMSH6, and hMLH1. Twenty-three out of the 110 patients (20.9%), 12 males and 22 females, aged 57 (47 - 94), had MSI. Seven germline mutations were found in these 23 MSI patients, accounting for 6.4% among the 110 CRC patients, including 3 cases of hMSH2 mutation, 3 cases of hMSH6 mutation, and 1 case of mutation of hMLH1. Screened by revised Bethesda guideline, the rate of MSI CRC is 20.9% and the rate of HNPCC is 6.4%. The missence germline mutations of hMSH2 and hMSH6 are more common in the Chinese patients with CRC.

Detection of Metachronous Neoplasms in Colorectal Cancer Patients: Identification of Risk Factors

Patients with colorectal cancer have a high risk of developing metachronous neoplasms. Identification of predictive factors associated with such conditions would allow individualized follow-up strategies in these patients. This study was designed to identify individual and familial factors associated with the development of metachronous colorectal neoplasms in patients with colorectal cancer. In the context of a prospective, multicenter, general population-based study-the EPICOLON project-all patients with colorectal cancer attended in ten Spanish hospitals during a one-year period were included. Patients with familial adenomatous polyposis or inflammatory bowel disease were excluded. All patients were monitored by colonoscopy within two years of the diagnoses. Demographic, clinical, pathologic, molecular (microsatellite instability status and immunohistochemistry for MSH2 and MLH1), and familial characteristics (fulfillment of Amsterdam I or II criteria, and revised Bethesda guidelines) were analyzed. A total of 353 patients were included in the study. At two years of follow-up, colonoscopy revealed the presence of adenomas in 89 (25 percent) patients and colorectal cancer in 14 (3.9 percent) patients, in 7 cases restricted to anastomosis. Univariate analysis demonstrated that development of metachronous neoplasm (adenoma or colorectal cancer) was associated with personal history of previous colorectal cancer (odds ratio, 5.58; 95 percent confidence interval, 1.01-31.01), and presence of previous or synchronous adenomas (odds ratio, 1.77; 95 percent confidence interval, 1.21-3.17). Although nonstatistical significance was achieved, metachronisms were associated with gender (P<0.09) and differentiation degree (P<0.08). Multivariate analysis identified previous or synchronous adenomas (odds ratio, 1.98; 95 percent confidence interval, 1.16-3.38) as independent predictive factor. Neither presence of tumor DNA microsatellite instability nor family history correlated with the presence of metachronous neoplasms. Patients with previous or synchronous colorectal adenoma have an increased risk of developing metachronous colorectal neoplasms. Accordingly, this subgroup of patients may benefit from specific surveillance strategies.

Pathology Features in Bethesda Guidelines Predict Colorectal Cancer Microsatellite Instability: A Population-Based Study

The revised Bethesda guidelines for Lynch syndrome recommend microsatellite instability (MSI) testing all colorectal cancers in patients diagnosed before age 50 years and colorectal cancers diagnosed in patients between ages 50 and 59 years with particular pathology features. Our aim was to identify pathology and other features that independently predict high MSI (MSI-H). Archival tissue from 1098 population-based colorectal cancers diagnosed before age 60 years was tested for MSI. Pathology features, site, and age at diagnosis were obtained. Multiple logistic regression was performed to determine the predictive value of each feature, as measured by an odds ratio (OR), from which a scoring system (MsPath) was developed to estimate the probability a colorectal cancer is MSI-H. Fifteen percent of tumors (162) were MSI-H. Independent predictors were tumor-infiltrating lymphocytes (OR, 9.1; 95% confidence interval [CI], 5.9-14.1), proximal subsite (OR, 4.7; 95% CI, 3.1-7.3), mucinous histology (OR, 2.8; 95% CI, 1.7-4.8), poor differentiation (OR, 1.9; 95% CI, 1.2-3.1), Crohn's-like reaction (OR, 1.9; 95% CI, 1.2-2.9), and diagnosis before age 50 years (OR, 1.9; 95% CI, 1.3-2.9). MsPath score >or=1.0 had a sensitivity of 93% and a specificity of 55% for MSI-H. The probability an individual colorectal cancer is MSI-H is predicted well by the MsPath score. There is little value in testing for DNA mismatch repair loss in tumors, or for germline mismatch repair mutations, for colorectal cancers diagnosed in patients before age 60 years with an MSPath score <1 (approximately 50%). Pathology can identify almost all MSI-H colorectal cancers diagnosed before age 60 years.

Assessing the Predictive Accuracy of hMLH1 and hMSH2 Mutation Probability Models

Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by a susceptibility to colorectal and extra-colonic cancers. Several guidelines exist for the identification of families suspected of having HNPCC, however these guidelines lack adequate sensitivity and specificity. In an attempt to improve accuracy for the detection of individuals with HNPCC, the Wijnen pre-test probability model (1998) and Myriad Genetics Laboratory prevalence table (2004) were developed. Here we evaluate the Wijnen model and Myriad table at predicting the presence of a mutation in individuals undergoing genetic testing for HNPCC. Forty-nine patients who had undergone genetic testing for germline mutations in hMLH1 and/or hMSH2 were part of our analysis. Our results revealed that the revised Bethesda guidelines performed with the highest sensitivity for germline mutations (94.4%), however the specificity was low (12.9%). Using a 10.0% mutation probability threshold, the Wijnen model and Myriad table had sensitivities of 55.6 and 60.0%, respectively and specificities of 54.8 and 23.8%, respectively. The Wijnen model and Myriad table were poor predictors of mutation prevalence, which is shown by the areas underneath their corresponding receiver operator characteristic curves (0.616 and 0.400, respectively). The results of this study demonsrate that neither the Wijnen model nor the Myriad table are sensitive or specific enough to be used as the only indication when to offer genetic testing for HNPCC.

N-Acetyltransferase (NAT) 2 acetylator status and age of tumour onset in patients with sporadic and familial, microsatellite stable (MSS) colorectal cancer

N-Acetyltransferase (NAT) 2 is an important enzyme involved in the metabolism of different xenobiotics, including potential carcinogens. Allelic variants of the NAT2 gene are determined by a pattern of single nucleotide polymorphisms (SNPs) resulting in slow (SA), intermediate (IA) or rapid acetylator (RA) phenotypes and causing the individual differences in the NAT2 metabolic capacity. To clarify the potential modifying role of the NAT2 acetylator status in microsatellite stable (MSS) colorectal cancer (CRC), we studied 140 patients with sporadic CRC (group 1) and 69 patients with CRC who met at least one criterion of the revised Bethesda guidelines (group 2). We did not observe any significant difference in the NAT2 acetylator status frequency between patients in both groups and 100 healthy controls (P=0.486). Regardless of a younger median age of tumour onset (AO) of 41 years in group 2 patients compared to 64 years in group 1 patients, no significant difference in AO was found between RA and SA status patients in both groups. The median AO in group 1 was 65 years in patients with RA and 63 years with SA status (P=0.065). The median AO in group 2 was 40 years in patients with RA and 42 years with SA status (P=0.814). Multivariate Cox regression analysis revealed that neither the NAT2 acetylator status (P=0.064 and 0.810, respectively) nor the gender (P=0.165 and 0.918, respectively) was a risk factor for the AO in both groups. These data do not support the hypothesis that the NAT2 acetylatorship acts as a modifying factor on the AO in sporadic and familial, microsatellite stable CRC.

Frequency of familiar cancer in a cohort of newly-diagnosed patients with colorectal cancer

13588 Background: Incidence on Hereditary Non Poliposis Colorectal Cancer (HNPCC) is 3–5% of all colorectal cancers (CRC). Primary identification of patients (p) with high risk of this hereditary syndrome is the first step before genetic testing for MSH2, MLH1 or MSH6 mutations. AIMS: To determine the frequency of family history of CRC in our population Methods: We have assessed cancer history (full family pedigree, including at least 2 generations of ascendants plus all descendants) in a cohort of 100 newly-diagnosed p with CRC cancer seen as first visit at the Division of Medical Oncology of the University Hospital of Zaragoza, Spain, from 2005. We have used the revised Bethesda Guideline for HNPCC published in JNCI (Vol 96. Feb 2004) Results: Median age was 72 (range: 26 - 85). 29 females/71 males. Considering Bethesda criteria for genetic testing, percentages of families fulfilling them were: Cancer before age 50: 7 (7%), synchronous/metachronous cancer: 1 (1%), other HNPCC associated tumors before age 50: 1 (ovarian 1%), One first-degree relative with HPNCC related tumor before age 50: 4 (4%), Two or more family members with HNPCC related cancer: 5 (5%). Overall, 14 (14%) fulfilled at least 1 of these criteria. Number of cases of tumors in the family (for a total of 909 family members) was 82, 10 cases of breast cancer, 23 of colorectal, 6 of gastric, 5 of prostate, 3 gynecologic, 11 lung, and 21 others. Conclusions: Frequency of familiar CC in unselected breast cancer patients of Zaragoza, Spain, is substantially higher than that expected. Assessment of cancer familiar history in the newly-diagnosed patients with CC cancer, helps us to identify families in which a genetic study is to be considered, and this could be useful to prevent new case of cancer. No significant financial relationships to disclose.

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

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. To compare the clinical performance of original and revised Bethesda guidelines for the detection of MSH2/MLH1 gene carriers in patients with colorectal cancer. 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. 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%). 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.

New Developments in Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Mismatch Repair Gene Testing

New Developments in Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Mismatch Repair Gene Testing