Maurizio Ponz de Leon

Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts

Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.

Microsatellite Instability and Colorectal Cancer Prognosis

Purpose: Many studies have evaluated the role of high levels of microsatellite instability (MSI) as a prognostic marker and predictor of the response to chemotherapy in colorectal cancer (CRC); however, the results are not conclusive. The aim of this study was to analyze the prognostic significance of high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based chemotherapy. Experimental Design: In three different institutions, 1,263 patients with CRC were tested for the presence of MSI, and CRC-specific survival was then analyzed in relation to MSI status, chemotherapy, and other clinical and pathologic variables. Results: Two hundred and fifty-six tumors were MSI-H (20.3%): these were more frequently at a less advanced stage, right-sided, poorly differentiated, with mucinous phenotype, and expansive growth pattern than microsatellite stable carcinomas. Univariate and multivariate analyses of 5-year–specific survival revealed stage, tumor location, grade of differentiation, MSI, gender, and age as significant prognostic factors. The prognostic advantage of MSI tumors was particularly evident in stages II and III in which chemotherapy did not significantly affect the survival of MSI-H patients. Finally, we analyzed survival in MSI-H patients in relation to the presence of mismatch repair gene mutations. MSI-H patients with hereditary non–polyposis colorectal cancer showed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis, this difference disappeared. Conclusions: The type of genomic instability could influence the prognosis of CRC, in particular in stages II and III. Fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients. The survival benefit for patients with hereditary non–polyposis colorectal cancer is mainly determined by younger age and less advanced stage as compared with sporadic MSI-H counterpart.

Muir-Torre syndrome

Muir-Torre syndrome is an autosomal-dominant skin condition of genetic origin, characterised by tumours of the sebaceous gland or keratoacanthoma that are associated with visceral malignant diseases. The cutaneous characteristics of Muir-Torre syndrome are sebaceous adenoma, epithelioma, carcinoma, or multiple keratoacanthomas, whereas visceral malignant diseases include colorectal, endometrial, urological, and upper gastrointestinal tumours. Although Muir-Torre syndrome has a striking familial association and features of autosomal-dominant transmission, it can arise in individuals without a family history or any known mutations. Clinical and biomolecular evidence has suggested that there are two types of Muir-Torre syndrome. The most common is a variant of hereditary non-polyposis colorectal cancer, which is characterised by defects in mismatch repair genes and early-onset tumours. The second type does not show deficiency in mismatch repair and its pathogenesis remains undefined. Diagnosis of these rare sebaceous lesions warrants the search for associated internal malignant diseases: the peculiarity of skin lesions and their biomolecular characterisation with microsatellite instability analysis and immunohistochemistry could be used to identify familial Muir-Torre syndrome, allowing clinicians to tailor a personalised programme to screen for skin and visceral malignant diseases in high-risk individuals.

Identification of Lynch syndrome among patients with colorectal cancer.

CONTEXT Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear. OBJECTIVE To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands. DESIGN, SETTING, AND PATIENTS Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data. MAIN OUTCOME Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening). RESULTS Of 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach. CONCLUSION Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.

Familial occurrence of gastric cancer in the 2-year experience of a population-based registry

The authors studied the familial occurrence of tumors in 154 individuals with gastric cancer by reviewing the clinical data and the genealogical tree of all patients registered in 1986 through 1987 in the Local Health Care District of Modena, Italy, for cancer of the stomach. Crude and age‐adjusted (world population) incidence rates of gastric cancer were 34.0 and 21.4 new cases/100,000/year, respectively, in men, and 24.5 and 10.9 in women, respectively. Among first‐degree relatives of the registered patients there were 30 cases of gastric carcinoma versus 15 cases in a control group matched for age and sex (Mantel‐Haenszel odds ratio [M‐H OR] 3.14, P < 0.01). This excess of gastric neoplasms was observed in siblings (17 versus 7, MH OR 4.33, P < 0.02) but not in parents (13 versus 8, not significant). Besides gastric cancer, there was no significant excess of other type of tumors in case families. The familial occurrence of gastric cancer tended to be more frequent in patients with “diffuse” carcinoma (52%) than in subjects with “intestinal” cancer (33%), although the difference was not statistically significant. In conclusion, the current investigation suggests that a “family history” for gastric neoplasms is usually observed in approximately 10% to 15% of the registered cases. As already described for other common malignancies, therefore, the familial occurrence of gastric carcinoma suggests the existence of a genetic susceptibility to cancer of the stomach, at least in a fraction of these patients.

Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas

Biallelic germline mutations in the base excision repair gene MYH have been reported in patients with multiple colorectal adenomas and cancer and in sporadic FAP patients not showing a detectable APC germline mutation. In this study, the prevalence of the common Y165C and G382D germline variants of the MYH gene was examined in 70 FAP/AAPC patients with no detectable APC mutation and a family history compatible with recessive inheritance. In addition, 141 normal‐population adenoma patients (mean number of adenomas, 2.8; range, 1–9) and 52 clean colon controls were studied. The entire coding region of the MYH gene was analyzed in Y165C or G382D heterozygous patients. Since the same second mutational event (a 3 bp deletion in exon 14, 1395delGGA) was detected in 3 patients, the prevalence of this variant was also examined in all groups. In all, 14 of 70 patients in the FAP/AAPC group (20%; 95% CI = 11.7–31.6%) had biallelic germline MYH variants and 3 were heterozygotes (4.3%). None of the 141 normal‐population adenoma patients carried biallelic germline MYH variants (95% CI = 0.06–4.1%) and 3 were heterozygotes (2.1%). In the control group, no MYH variants were detected. These results indicated that MYH‐associated polyposis (MAP) is present in about 20% of Italian FAP/AAPC patients, in whom no germline APC mutation is detectable and showing a family history compatible with recessive inheritance, and in a small fraction of patients with colorectal adenomas in the general population. In addition, our data suggest that mutation 1395delGGA is a subpolymorphic MYH mutational event in some Caucasian populations.

Antioxidant vitamins or lactulose for the prevention of the recurrence of colorectal adenomas

Colonic adenomas represent the natural precursor lesions of most colorectal cancers. The treatment of choice is endoscopic polypectomy. However, after endoscopic removal, polyps recur in a large fraction of cases. Thus, we evaluated the effect of antioxidant vitamins or lactulose on the recurrence rate of adenomatous polyps. After polypectomy, 255 individuals were randomized into three groups. Group 1 was given vitamin A (30,000 IU/ day), vitamin C (1 g/day), and vitamin E (70 mg/day); Group 2 was given lactulose (20 g/day); Group 3 received no treatment. Forty-six subjects had to be excluded because the histologic diagnosis was not consistent with adenoma. The remaining 209 individuals were included in the analysis according to the “intention to treat” criterion, though 34 did not adhere to the scheduled treatment or were lost during the follow-up. Subjects were followed at regular intervals for an average of 18 months. Polyps recurring before one year from index colonoscopy were considered missed by the endoscopist. In the 209 evaluable subjects, the percentages of recurrence of adenomas were 5.7 percent, 14.7 percent, and 35.9 percent in the vitamins, lactulose, and untreated groups, respectively. The fraction of subjects remaining free of adenomas, estimated by Kaplan-Meier survival curves, was significantly different among the three groups (log-rank chisquared =17.138;P< 0.001). Using Coxs regression analysis, treatment was the only variable that significantly contributed to the model (regression coefficient=0.905;P<0.001). In conclusion, either antioxidant vitamins or, to a lesser extent, lactulose lower the recurrence rate of adenomas of the large bowel and can be proposed as chemopreventive agents, at least in high-risk individuals.

Incidence and familial occurrence of colorectal cancer and polyps in a health-care district of Northern Italy

The first year of registration of colorectal tumors in a predominantly urban population (263,546 inhabitants) of northern Italy gave us the opportunity to investigate: (a) the incidence (crude, age‐specific, age‐standardized) of both colorectal cancer and polyps and their localization; (b) the familial occurrence of these neoplasms; and (c) if the data could fit into the “Adenoma‐Carcinoma Sequence.” Crude incidence of cancer was 52.8 new cases/100,000 in 1984, with 53.4 cases in men and 52.2 cases in women. The corresponding figures for polyps were 59.6 new cases, with 83.4 in men and 37.3 cases in women. The incidence increased with age for both cancer and polyps, although the latter were more frequent until patients were in their sixties and the peak of incidence of polyps anticipated that of cancer by a 5 year period. Both cancer and polyps had a similar distribution in the large bowel, more than 60% being located in the left distal portion. There were 72 cases of colorectal cancer among the first‐degree relatives of the registered patients compared with 16 in the controls (RR = 4.26, χ2 = 27.2 p < 0.001). An increased frequency of cases of colorectal cancer in the families was found in both the cancer group and the polyp group. In conclusion, the observed incidence of large bowel tumors was similar to that of other well‐developed countries. The earlier rise and peak of age‐specific incidence of polyps as compared to cancer, the similar distribution of benign and malignant neoplasms in the various intestinal tracts, and the similar familial aggregation observed both in the cancer and in the polyp groups further support the “polyp‐cancer sequence” and provide us with a promising strategy for the prevention of colorectal malignancies.

Identification of Muir-Torre Syndrome among Patients with Sebaceous Tumors and Keratoacanthomas Role of Clinical Features, Microsatellite Instability, and Immunohistochemistry

The Muir–Torre syndrome (MTS) is an autosomal‐dominant genodermatosis characterized by the presence of sebaceous gland tumors, with or without keratoacanthomas, associated with visceral malignancies. A subset of patients with MTS is considered a variant of the hereditary nonpolyposis colorectal carcinoma, which is caused by mutations in mismatch‐repair genes. The objective of the current study was to evaluate whether a combined clinical, immunohistochemical, and biomolecular approach could be useful for the identification of Muir–Torre syndrome among patients with a diagnosis of sebaceous tumors and keratoacanthomas.

Molecular Screening for Hereditary Nonpolyposis Colorectal Cancer: A Prospective, Population-Based Study

PURPOSE Germline mutations in mismatch repair genes predispose to hereditary nonpolyposis colorectal cancer (HNPCC). To address effective screening programs, the true incidence of the disease must be known. Previous clinical investigations reported estimates ranging between 0.5% and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular studies in Finland found an incidence of 2% to 2.7% of mutation carriers for the disease. The aim of the present report is to establish the frequency of the disease in a high-incidence area for colon cancer. PATIENTS AND METHODS Through the data of the local CRC registry, we prospectively collected all cases of CRC from January 1, 1996, through December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9% of the incident cases) were screened for microsatellite instability (MSI) with six to 12 mono- and dinucleotide markers. MSI cases were subjected to MSH2 and MLH1 germline mutation analysis and immunohistochemistry; the methylation of the promoter region was studied for MLH1. RESULTS Twenty-eight cases (8.3% of the total) showed MSI. MSI cases differed significantly from microsatellite-stable (MSS) cases for their proximal location (P <.01), high mucinous component (P <.01), and poor differentiation (P =.002). Of MSI cases studied (n = 12), only one with a family history compatible with HNPCC had a germline mutation (in MSH2). Five other patients with a family history of HNPCC (two with MSI and three with MSS tumors) did not show germline mutations. CONCLUSION We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.