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Background: Hereditary non-polyposis colorectal cancer (HNPCC) arises mostly from germline mutations of the mismatch repair genes MSH2 and MLH1. The diagnosis of HNPCC is based on a set of clinical criteria that may be too restrictive to identify all affected patients. Immunohistochemical staining (IHC) for the mismatch repair proteins, MutS homologue 2 (MSH2) and MutL homologue 1 (MLH1), reliably identifies the microsatellite instability phenotype. This study evaluated the ability of IHC to detect germline mutations in an unselected group of patients with colorectal cancer (CRC)., Methods: All patients with CRC operated on between July 2000 and March 2003, and demonstrating a loss of protein, were contacted. Following informed consent, searchs for germline mutation and methylation of the promoter were performed on normal and tumoral DNA., Results: Thirty patients agreed to participate, four of whom fulfilled the Amsterdam II criteria. Loss of expression of MLH1 was found in 20 patients, and loss of expression of MSH2 in ten patients. Four of the MLH1-deficient patients had a germline MLH1 point mutation (positive predictive value (PPV) 20 (95 per cent confidence interval (c.i.) 2 to 38 per cent) and 11 had promoter methylation. Seven of the MSH2-deficient patients had a germline MSH2 point mutation (PPV 70 (95 per cent c.i. 54 to 96 per cent), and none showed promoter methylation., Conclusion: MLH1-deficient patients who are young or have a positive family history of cancer should be referred for genetic testing and counselling, whereas MSH2-deficient patients should be counselled in the same way as patients with HNPCC., (Copyright (c) 2007 British Journal of Surgery Society Ltd.)

Objective: The aim of this study was to determine the frequency of MYH mutations in one large population of polyposis patients without APC mutation identified., Summary Background Data: Familial adenomatous polyposis (FAP) is the most known inherited colorectal cancer syndrome. In 70% to 80% of polyposis patients, an APC mutation is found. Patients with polyposis but no APC mutation are considered as APC-muted patients and followed as their relatives accordingly. Biallelic mutation of MYH has been found to responsible of colorectal polyposis and cancer in an autosomal recessive pattern of inheritance., Methods: Between 1978 and 2004, 433 patients were operated for polyposis. A mutation on APC was identified in 322 patients. Among the remaining patients, 44 were identified as possible MYH-muted patients and contacted, and 31 signed informed consent. Clinical data were obtained from the patients' medical notes. Germline mutation of MYH was searched by sequencing the whole gene. To confirm the deleterious effects of biallelic MYH mutation, transversions on K-ras and APC were searched., Results: There were 9 women and 22 men with a mean age of 53.9 years (range, 22-68 years) at the time of diagnosis. The mean number of polyps was 62.8 (range, 11-266). Eighteen patients (58.1%) had a colorectal cancer. We found biallelic MYH mutation in 6 patients (19.3%; 95% confidence interval, 5.2%-33.5%) and 5 (83.3%) had transversions in K-ras and/or APC., Conclusion: MYH is a new gene responsible for about 1.4% of all adenomatous polyposis and about 20% of adenomatous polyposis without APC mutation identified. Search for MYH biallelic mutation in these patients should be systematic as it changes their and relatives'surveillance.

Purpose: The purpose of this study was to determine whether preoperative radiotherapy had an influence on the urinary and sexual function of patients having a sphincter-saving, nerve-preserving total mesorectal excision., Methods: Urinary and sexual function of male patients undergoing sphincter-saving, nerve-preserving total mesorectal excision for primary resectable rectal carcinoma between January 1998 and December 1999 were evaluated retrospectively. Assessment was by standardized questionnaires., Results: Fifty male patients met the inclusion criteria. Three patients had died (hepatic metastases), and five were living outside the European community and could not be contacted. Sixteen patients underwent preoperative radiotherapy (Group 1), and 26 patients were not treated preoperatively (Group 2). There was no perioperative mortality. Age, tumor stage, and localization of the tumor were comparable. Median follow-up was 20 months. Urinary function was not significantly different. One patient in Group 1 and 2 patients in Group 2 were impotent before surgery. All remaining patients in Group 2 (n = 24) and 11 of 15 remaining patients in Group 1 were sexually active (P = 0.016). All sexually active patients (n = 24) in Group 2 and 9 of the 11 sexually active patients in Group 1 have normal ejaculation (P = 0.09)., Conclusion: Preoperative radiotherapy for primary resectable rectal carcinoma treated by total mesorectal excision with autonomic nerve preservation may impair male sexual function.

Objectives: To determine the prevalence of adenomas in ileal pouches from patients with familial adenomatous polyposis (FAP) and to determine whether a correlation exists between the presence of pouch adenomas and duodenal adenomas and the site of the adenomatous polyposis coli gene mutation., Summary Background Data: Restorative proctocolectomy can markedly reduce the risk of colorectal adenocarcinoma in FAP patients. However, adenomas with the potential to progress to adenocarcinoma can develop in the duodenum, ileum, and continent ileostomy after restorative proctocolectomy. More recently, adenomas have been described in the ileal pouch after ileoanal anastomosis., Methods: Pouch endoscopy was offered to 167 patients with FAP who had undergone restorative proctocolectomy between January 1984 and December 1996., Results: Adenomas were found in 35% of the 85 ileal pouches examined. No invasive carcinomas were noted. The risk of developing one or more adenomas at 5, 10, and 15 years was 7%, 35%, and 75%, respectively. Patients with adenomas were more likely to have duodenal and ampullary adenomas. No correlation was detected between adenoma development and the site of the adenomatous polyposis coli mutation., Conclusions: Adenomas are frequently found in the ileal pouch of patients after restorative proctocolectomy for FAP. Regular endoscopic surveillance of the pouch is recommended at a frequency similar to that of upper gastrointestinal endoscopy.

Microsatellites are tandem repeats of simple sequences that occur abundantly and are randomly interspersed throughout the human genome. They typically consist of 10-50 copies of 1-6 bp motifs, and are characterized by a high degree of polymorphism. Despite the variability observed among individuals, microsatellite are replicated faithfully at each cell division in normal germline and somatic cells (1).

Purpose: Virtually all untreated patients with familial adenomatous polyposis develop colorectal carcinoma. Thus, prophylactic colectomy is indicated. Detractors of ileal pouch-anal anastomosis prefer ileorectal anastomosis for teenagers because of the potential negative impact of ileal pouch-anal anastomosis on quality of life. The aim of this study was to assess the effects on quality of life of ileal pouch-anal anastomosis in teenagers with familial adenomatous polyposis., Methods: Between 1981 and 1998, 48 teenagers underwent ileal pouch-anal anastomosis for familial adenomatous polyposis. One patient had proctectomy and ileal pouch-anal anastomosis after previous ileorectal anastomosis. A temporary diverting loop ileostomy was established in 42 patients (87.5 percent). One patient had colonic carcinoma diagnosed preoperatively. Two other patients were found to have unsuspected rectal cancer at surgery. Mean follow-up (+/- standard deviation) in 43 patients was 80.5 +/- 42 months., Results: There was no immediate postoperative mortality. Postoperative complications included pelvic sepsis (3 patients; 1 requiring reoperation) and bleeding (1 patient; no surgery required). One patient died of metastatic colonic carcinoma. Ten patients required reoperation, seven had bowel obstruction, one had portal hypertension, and two required an ileostomy. The mean (+/- standard deviation) daytime and nighttime stool frequency was 4 +/- 1.5 and 1 +/- 1, respectively. One patient reported daytime and nighttime incontinence, and two patients reported nighttime incontinence only. No patient experienced impotence or retrograde ejaculation. Social, sexual, sport, housework, recreation, family, travel, and work activities were improved or unchanged in 82.5, 87, 80, 90, 80, 92.5, 77.5, and 89 percent of patients, respectively. Three male patients fathered children, and three female patients had a total of six children after normal pregnancies and deliveries., Conclusion: The impact of ileal pouch-anal anastomosis on quality of life was favorable in the majority of teenagers. The risk of rectal cancer should be the major consideration before proposing an operation to teenagers with familial adenomatous polyposis.

Two microsatellite instability (MSI) phenotypes have been described in colorectal cancer (CRC): MSI-H (instability at >30% of the loci examined) and MSI-L (MSI at 1-30% of the loci examined). The MSI-H phenotype, observed in both hereditary nonpolyposis colon cancer-associated CRC and approximately 15% of sporadic CRC, generally results from mutational or epigenetic inactivation of the DNA mismatch repair (MMR) genes hMSH2 or hMLH1. The genetic basis for the MSI-L phenotype, however, is unknown. Several other proteins, including hMSH3 and hMSH6, also participate in DNA MMR. Inactivating mutations of MSH6 in yeast and human tumor cell lines are associated with an impaired ability to repair single-base mispairs and small insertion-deletion loops but not large insertion-deletion loops. This suggests that hMSH6 mutations are more likely to be associated with a MSI-L phenotype than a MSI-H phenotype in CRC. To explore this possibility, we screened tumors from 41 patients with MSI-L CRC for hMSH6 mutations with conformation-sensitive gel electrophoresis (CSGE) and for hMSH6 protein expression by immunohistochemistry. Alterations found with CSGE were confirmed by DNA sequencing of normal and tumor tissue. One somatic (Asp389Asn) and 15 germ-line changes were found. Of the 15 germ-line changes, 9 were found in an intron (none involving splice junctions), and 6 were found in an exon (Gly39Glu, Leu395Val, and 4 silent alterations). Immunohistochemical staining for hMSH6 performed on 34 of the 41 tumors revealed strong nuclear hMSH6 expression in all of the cases. Overall, our results suggest that hMSH6 mutations do not play a major role in the development of sporadic CRC with a MSI-L phenotype.

Endometrial cancer is the second most common malignancy in patients with hereditary nonpolyposis colorectal cancer (HNPCC). The age at diagnosis of HNPCC-associated endometrial cancer is approximately 15 years younger than for sporadic endometrial cancer. Our current study was undertaken to determine the frequency of microsatellite instability (MSI) and absence of hMLH1 or hMSH2 protein expression in young patients with endometrial carcinoma and to correlate these findings with histopathologic and clinical features. Endometrial carcinoma from 62 women (23-52 years, median age 46) were assessed for MSI. Twenty-one of the 62 (34%) tumors demonstrated MSI. Of the 21 tumors demonstrating MSI, 12 showed an absence of hMLH1 expression, 4 showed an absence of hMSH2 expression, and 5 demonstrated normal expression of both proteins. All 41 tumors without MSI demonstrated normal hMLH1 and hMSH2 expression. Two patients with MSI tumors fulfilled the Amsterdam criteria for HNPCC, while 2 had histories suggestive of HNPCC. None of the patients with tumors without MSI had a personal or family cancer history suggestive of HNPCC. The MSI phenotype was associated (p < 0.05) with high FIGO stage and grade, cribriform growth pattern, mucinous differentiation and necrosis. Our findings suggest that the frequency of HNPCC in young endometrial cancer patients is relatively low when compared with the frequency of HNPCC in young colorectal cancer patients. Defects of the MMR proteins hMSH2 or hMLH1 account for MSI in most but not all endometrial cancers from young patients.