Showing papers by "Francesc Balaguer published in 2011"
TL;DR: Patients with CIMP-positive colorectal tumors do not benefit from 5-FU-based adjuvant chemotherapy and are not an independent predictor of outcome.
195 citations
TL;DR: The discovery of unique miRNA expression profiles that can successfully discriminate between Lynch syndrome, sporadic MSI, and sporadic MSS colorectal cancers provides novel insights into the role of miRNAs in coloreCTal carcinogenesis, which may contribute to the diagnosis, prognosis, and treatment of this disease.
Abstract: Purpose: microRNAs (miRNA) are small noncoding transcripts that play an important role in carcinogenesis. miRNA expression profiles have been shown to discriminate between different types of cancers. The aim of this study was to analyze global miRNA signatures in various groups of colorectal cancers (CRC) based on the presence of microsatellite instability (MSI). Experimental Design: We analyzed genome-wide miRNA expression profiles in 54 CRC tissues [22 with Lynch syndrome, 13 with sporadic MSI due to MLH1 methylation, 19 without MSI (or microsatellite stable, MSS)] and 20 normal colonic tissues by miRNA microarrays. Using an independent set of MSI-positive samples (13 with Lynch syndrome and 20 with sporadic MSI), we developed a miRNA-based predictor to differentiate both types of MSI by quantitative reverse transcriptase PCR. Results: We found that the expression of a subset of nine miRNAs significantly discriminated between tumor and normal colonic mucosa tissues (overall error rate = 0.04). More importantly, Lynch syndrome tumors displayed a unique miRNA profile compared with sporadic MSI tumors; miR-622, miR-1238, and miR-192 were the most differentially expressed miRNAs between these two groups. We developed a miRNA-based predictor capable of differentiating between types of MSI in an independent sample set. Conclusions: CRC tissues show distinct miRNA expression profiles compared with normal colonic mucosa. The discovery of unique miRNA expression profiles that can successfully discriminate between Lynch syndrome, sporadic MSI, and sporadic MSS colorectal cancers provides novel insights into the role of miRNAs in colorectal carcinogenesis, which may contribute to the diagnosis, prognosis, and treatment of this disease. Clin Cancer Res; 17(19); 6239–49. ©2011 AACR .
112 citations
TL;DR: Novel evidence is provided that MSH3 deficiency contributes to the cytotoxicity of platinum drugs through deficient DSB repair, and these data lay the foundation for the development of effective prediction and treatments for cancers with MSH 3 deficiency.
82 citations
TL;DR: In the general nonselected population, the MsPath score accurately predicted the probability of bearing a MSI high CRC, but it was insufficiently accurate to use for the selection of patients warranting MLH1/MSH2 mutation testing in the setting of Lynch syndrome.
Abstract: Purpose Bethesda guidelines are used to recognize patients at risk for Lynch syndrome. However, obtaining personal and familial tumor data can sometimes be difficult. The Microsatellite Path Score (MsPath), a pathological score, based on age, tumor location, and pathologic features, has been developed to effectively predict colorectal cancer with DNA mismatch repair (MMR) deficiencies. However, the MsPath model’s performance in an unselected, population-based colorectal cancer (CRC) population is unknown. Patients and Methods We analyzed all patients with CRC regardless of age, personal or family history, and tumor characteristics from the EPICOLON study, an independent, prospective, multicenter, population-based cohort (N 1,222). All patients underwent tumor microsatellite instability (MSI) analysis and immunostaining for MLH1/MSH2, and those with MMR underwent tumor BRAF mutation analysis and MLH1/MSH2 germline testing. All the pathologic features were centralized and evaluated blinded to the MMR status. Results MsPath score for prediction of having MSI high, with the recommended MsPath cutoff score 1.0, had a sensitivity, specificity, and positive predictive value (PPV) of 92.8% (95% CI, 86.9 to 98.3), 64.1% (95% CI, 61.1 to 66.8), and 15.8% (95% CI, 12.2 to 18.6), respectively. MsPath score had a sensitivity, specificity, and PPV of 81.8% (95% CI, 59.0 to 99.8), 60.6% (95% CI, 57.8 to 63.4), and 1.9% (95% CI, 0.7 to 3.1), respectively, for the identification of MLH1/MSH2 gene carriers. Application of the MsPath score, resulted in two (18%) of 11 mutation carriers being missed, both pathogenic germline MSH2 mutations. Conclusion In the general nonselected population, the MsPath score accurately predicted the probability of bearing a MSI high CRC, but it was insufficiently accurate to use for the selection of patients warranting MLH1/MSH2 mutation testing in the setting of Lynch syndrome. J Clin Oncol 29:3374-3380. © 2011 by American Society of Clinical Oncology
19 citations
TL;DR: A novel duplication of exons 12 and 13 of the MLH1 gene was detected in two independent Lynch syndrome families from Colombia, and a putative founder effect and prescreening Lynch syndrome Antioquia families for this specific mutation could be suggested.
17 citations
TL;DR: Although it is welcome news that the authors now better understand the molecular pathogenesis of some proportion of sporadic cancers, nonetheless serrated polyps present with a major challenge for the early detection and management of colorectal cancer, which is no longer considered to be a homogenous entity.
Abstract: Serrated polyps of the colorectum are formed by a spectrum of lesions that share a unique histological feature- the presence of sawtooth-shaped crypts. In the last decade, significant advances have been made on deciphering the molecular differences between these morphologically similar lesions, which has paved path for our current understanding for their neoplastic potential. In particular, the sessile serrated adenoma has become to be recognized as the precursor lesion for the group of sporadic colorectal cancers with high levels of microsatellite instability. These recent findings have challenged the long-held fundamental paradigm that all colon cancers arise via the classic adenoma-carcinoma sequence. Although it is welcome news that we now better understand the molecular pathogenesis of some proportion of sporadic cancers, nonetheless serrated polyps present with a major challenge for the early detection and management of colorectal cancer, which is no longer considered to be a homogenous entity.
2 citations
TL;DR: Use of low dose aspirin is associated with about a 20% reduction in CRC incidence but this reduction is only evident after over 7 years of use, although this is a modest reduction aspirin combined with other agents such as calcium could result in a more substantial effect.
2 citations
TL;DR: Classification of serrated polyps is evolving and the fact that morphological changes in serrated lesions are linked to a preneoplastic behavior is highlighted, particularly important for colorectal cancer prevention.
Abstract: Until recently, all serrated polyps were classified simply as hyperplastic polyps and were thought to represent benign lesions with no progression to malignancy. However, the recognition during the last decade that some serrated polyps may progress to colorectal cancer through the “serrated neoplastic pathway” has changed the understanding of the significance of these lesions. Classification of serrated polyps is evolving and underscores the fact that morphological changes in serrated lesions are linked to a preneoplastic behavior. This fact has been observed not only in the hyperplastic polyposis syndrome, characterized by multiple or large serrated polyps, but also in the sporadic setting. These findings are particularly important for colorectal cancer prevention, and adequate surveillance programs tailored for patients with serrated polyps are urgently needed.
2 citations
2 citations
TL;DR: This study analyzed a panel of CRC cells with different metastatic potential, as well as tissues from 50 CRC patients with matched primary colon cancer and corresponding liver metastasis tissues, to determine the role of increased hypomethylation of Alu and LINE-1 sequences in CRC metastasis development.
Abstract: Background: Global hypomethylation of cytosines within CpG dinucleotides is one of the distinguishing features of the neoplastic cells in human cancers. More specifically, hypomethylation of evolutionarily conserved repetitive elements (Alu and LINE-1) is associated with increased chromosomal instability in colorectal cancer (CRC). Recent data indicates that transcription start sites of certain proto-oncogenes are located within these repeat elements, and increased hypomethylation of these regions may induce the expression of illegitimate oncogenic transcripts. Primary CRCs demonstrate frequent global Alu and LINE-1 hypomethylation; however, it is unclear whether hypomethylation of these repeat sequences may be associated with a metastatic phenotype Aim: This study was aimed to determine the role of increased hypomethylation of Alu and LINE-1 sequences in CRC metastasis development. Materials and Methods: We analyzed a panel of CRC cells with different metastatic potential, as well as tissues from 50 CRC patients with matched primary colon cancer and corresponding liver metastasis tissues. Alu and LINE-1 methylation levels were determined by quantitative bisulfite pyrosequencing. Results: Lower levels of Alu and LINE-1 methylation were observed in CRC cell lines that came from metastatic foci. When we analyzed Alu and LINE-1 methylation levels in clinical specimens, the levels of Alu methylation in liver metastatis were significantly lower compared to the matched primary CRC tissues (77.2%±8.3 and 80.9%±10.7, respectively; P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 95. doi:10.1158/1538-7445.AM2011-95
2 citations