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This trial tested the influence of aspirin or resistant starch on the incidence of colorectal cancer or colonic adenomas in patients with the Lynch syndrome (hereditary nonpolyposis colon cancer). Neither intervention influenced the incidence of colorectal neoplasms in the Lynch syndrome. Neither aspirin or resistant starch influenced the incidence of colorectal neoplasms in the Lynch syndrome. The regular use of aspirin or aspirin-like agents is associated with a moderate reduction in the risk of colonic polyps and colorectal cancer. 1 – 4 Randomized trials of high-fiber diets have not shown a reduction in the risk of adenomas or colorectal cancer, 5 but none have investigated the effects of resistant starch. There is epidemiologic evidence of a negative correlation between colon cancer and starch intake. 6 Resistant starches escape digestion in the upper gut; colonic fermentation yields short-chain fatty acids, including butyrate, which has antineoplastic properties. 7 In carcinogen-treated rats, resistant starch reduces the development of intestinal tumors 8 , 9 and the production . . .

Background: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours. Methods: This prospective multicentric study involved 251 stage I–III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12–13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4–9), CpG island methylation phenotype status, ploidy, S-phase, LOH. Results: The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS -mutated ( P =0.005), BRAF wt ( P =0.009) and pMMR tumours ( P =0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR ( P <0.001) and show higher DPD expression (median 14.9 vs 7.9, P =0.027) and EGFR content (median 69 vs 38, P =0.037) relative to pMMR. Conclusions: Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.

Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with BRCA1/2 or MMR genes mutation. Genetic testing and consultations for familial high-risk individuals are exclusively funded and monitored by the INCa in France. All nationwide cancer genetics centers reported annually standardized parameters of activity from 2003 to 2011. The analysis included a total of 240,134 consultations and 134,652 genetic tests enabling to identify 32,494 mutation carriers. Referral for hereditary breast and ovarian cancer (HBOC) or colorectal cancer predisposition syndromes represented 59 % (141,639) and 23.2 % (55,698) consultations, respectively. From 2003 to 2011, we found a dramatic and steady increase of tests performed for BRCA1/2 (from 2,095 to 7,393 tests/year, P  < 0.0001) but not for MMR genes (from 1,144 to 1,635/year, P  = NS). The overall percentage of deleterious mutations identified in the probands tested was 13.8 and 20.9 % in HBOC and Lynch syndromes, respectively. Pooled analysis for BRCA1/2 and Lynch syndrome tests showed an inverse relationship between the percentage of mutation detected and the absolute number of tests performed over the time (overall Cochran–Armitage test for trend: P  < 0.001). In families with BRCA1/2 or MMR identified mutations, there was an average number of 2.94 and 3.28 relatives performing targeted tests, respectively. This nationwide study shows a lack of referral and genetic testing in Lynch as compared to HBOC syndromes. Only a third of relatives of a proband with a predisposing mutation performed a targeted test. Enhanced information about benefit of genetic testing should be given to clinicians and patients for Lynch syndrome and relatives of a proband carrying an identified predisposing mutation.

[...]the absence of significant genotype-phenotype correlation justifies the clinical evaluation of a unique surveillance protocol in the case of MSH2 or MLH1 germline mutations that might be initiated from the start of adulthood for colorectal cancer risk and at 30 years for other sites. [...]because endometrial cancer is the first presenting symptom for a quarter of gene carrier females, a personal or familial history compatible with HNPCC disease should be systematically investigated.

Germline mutations of the STK11/LKB1 tumour suppressor gene (19p13.3) are responsible for Peutz-Jeghers syndrome (PJS), a rare genetic disorder, which is dominantly inherited. In addition to the typical hamartomatous gastrointestinal polyps and perioral pigmented lesions, PJS is also associated with the development of tumours in various sites. No specific follow up has yet been evaluated for gene carriers. Furthermore, genetic heterogeneity has been reported, which makes genetic counselling difficult. We report here the analysis of the STK11/LKB1 locus in a series of 34 PJS families, combining the search for mutations and rearrangements in the coding sequence, allele specific expression tests, and linkage studies. Germline deleterious mutation of the STK11/LKB1 gene were identified in 70% of cases. The hypothesis of a second PJS locus was reinforced and PJS families could be divided into two groups on the basis of the presence or absence of an identified STK11/LKB1 alteration. Analysis of clinical data indicates that the cancer associated risk is markedly different in the two groups. PJS patients with no identified STK11/LKB1 mutation are at major risk for proximal biliary adenocarcinoma, an infrequent tumour in the general population. Up to 30% of PJS patients are caused by mutation in an unidentified gene that confers high susceptibility to cancer development.

Tissue microarray technology enables the analysis of hundreds of specimens by arranging numerous 0.6-mm tissue core biopsy specimens into a single paraffin block. Validation studies are necessary to evaluate the representativeness of small disks taken from the original tissue. We validated the tissue microarray technology in colorectal carcinoma by analyzing the immunohistochemical expression of proteins involved in the two main pathways of colorectal carcinogenesis: p53 protein for loss of heterozygosity tumors, hMLH1 and hMSH2 proteins for microsatellite instability (MSI) tumors. We compared in 30 colorectal carcinomas (15 MSI(-) and 15 MSI(+)), 8 microarrays disks, and the whole section of the block from which they were derived. Tumoral tissue was present in 95.7% of the microarray disks. The analysis of three disks per case was comparable to the analysis of the whole section in 99.6% (p53), 98.8% (hMLH1), and 99.2% (hMSH2) of cases. In the second part we applied the tissue microarray technology to 263 consecutive cases of colorectal carcinoma, sampled by three cores. We showed that 48.5% overexpressed p53 and 8.7% lost hMLH1 or hMSH2. Tissue microarray technology, validated in colorectal carcinoma, appears as a useful research tool for rapid analysis of the clinical interest of molecular alterations.

The t(8;16)(p11;p13) is a rare translocation involved in de novo and therapy-related myelomonocytic and monocytic acute leukemia. It fuses two genes encoding histone acetyltransferases (HATs), MYST3 located at 8p11 to CREBBP located at 16p13. Variant translocations involve other HAT-encoding genes such as EP300 , MYST4 , NCOA2 or NCOA3 . MYST3-linked acute myeloid leukemias (AMLs) share specific clinical and biological features and a poor prognosis. Because of its rarity, the molecular biology of MYST3-linked AMLs remains poorly understood. We have established the genome and gene expression profiles of a multicentric series of 61 M4/M5 AMLs including 18 MYST3-linked AMLs by using array comparative genome hybridization (aCGH) ( n =52) and DNA microarrays ( n =44), respectively. We show that M4/5 AMLs have a variety of rare genomic alterations. One alteration, a gain of the MYB locus, was found recurrently and only in the MYST3-linked AMLs (7/18 vs 0/34). MYST3-AMLs have also a specific a gene expression profile, which includes overexpression of MYB, CD4 and HOXA genes. These features, reminiscent of T-cell acute lymphoid leukemia (ALL), suggest the targeting of a common T-myeloid progenitor.

The objective of this study was to report the value of diagnostic hysteroscopy and endometrial biopsy for the detection of complex atypical hyperplasia or cancer in asymptomatic human non-polyposis colon cancer (HNPCC) patients. The secondary objective was to evaluate the accuracy of hysteroscopy, using endometrial biopsy as a gold standard. Consecutive patients at risk of HNPCC evaluated between January 1, 1999, and June 30, 2006 were included if they underwent diagnostic hysteroscopy at least once. Patients with a history of hysterectomy and those unwilling to undergo diagnostic hysteroscopy were not included. Yearly follow-up evaluations included diagnostic hysteroscopy, with endometrial biopsy. Hysteroscopic and histologic findings were recorded and compared. We included 62 patients, of whom 13 had mismatch repair gene mutations and 49 met Amsterdam II criteria. Of 125 attempted hysteroscopies, 11 (8%) failed. Hysteroscopy showed normally appearing mucosa in 46 cases, nonmalignant lesions in 65 cases, and possibly malignant lesions in 3 cases with abnormal uterine bleeding. Endometrial biopsy was attempted in 116 cases and failed in 12 (10%). Three cases each of simple hyperplasia and of cancer were diagnosed. No preinvasive or invasive lesions were found in asymptomatic women. When compared to endometrial biopsy, sensitivity of hysteroscopy was 100% for the detection of hyperplasia or cancer. No cases of cancer were diagnosed in asymptomatic patients in our study. However, diagnostic hysteroscopy ensured the diagnosis of endometrial adenocarcinoma in HNPCC women with bleeding. Nevertheless, usefulness and optimal modalities of screening remain to be determined.