Hospital Universitario Elche

Alicante, Spain

Hospital Universitario Elche

Alicante, Spain
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Castillejo A.,Hospital Universitario Elche | Guarinos C.,Hospital Universitario Elche | Martinez-Canto A.,Hospital Universitario Elche | Barbera V.,Hospital Universitario Elche | And 18 more authors.
BMC Medical Genetics | Year: 2011

Background: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS.Methods: The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers.Results: Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients.Conclusions: The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives. © 2011 Castillejo et al; licensee BioMed Central Ltd.


Egoavil C.M.,Hospital Universitario Elche | Egoavil C.M.,Hospital Naval | Montenegro P.,Instituto Nacional Enfermedades Neoplasicas INEN | Soto J.L.,Hospital Universitario Elche | And 11 more authors.
Pathology | Year: 2011

Background: The incidence of colorectal cancer (CRC) in Peru has been increasing, and no data have been published on the molecular features. We explored the most relevant genetic events involved in colorectal carcinogenesis, with clinical implications. Methods: Using immunohistochemistry for mismatch-repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) and microsatellite instability analysis, we evaluated the status of 90 non-selected CRC Peruvian patients followed in a nationwide reference hospital for cancer (INEN, Lima). Tumours with loss of hMLH1 were evaluated further for hMLH1 promoter hypermethylation and all cases were evaluated for the presence of KRAS and BRAF-V600E mutations. Results: MMR deficiency was found in 35 (38.8%) patients. We identified an unexpected association between MMR deficiency and older age. Among the 14 cases with lossof MLH1, 10 samples exhibited hypermethylation. Of the 90 cases evaluated, 15 (16.7%) carried KRAS mutations; we found one previously unreported mutation (G13R). Conclusions: Peruvian CRC tumours exhibited the highest prevalence of MMR deficiency reported to date. The expected hereditary component was also high. The age of onset of these MMR deficient tumours was greater than that observed for non-MMR deficient cases, suggesting the ineffectiveness of the Bethesda criteria for Lynch syndrome screening in Peru. Prospective studies are warranted to define the molecular characteristics of CRC in this population. © 2011 Royal College of Pathologists of Australasia.


Esteban F.,Hospital Clinico San Carlos | Cerdan F.J.,Hospital Clinico San Carlos | Garcia-Alonso M.,Hospital Clinico San Carlos | Sanz-Lopez R.,Hospital Clinico San Carlos | And 6 more authors.
Colorectal Disease | Year: 2014

Aim: The introduction of multimodal or fast track (FT) rehabilitation and laparoscopy in colorectal surgery has improved patient recovery and shortened hospital stay (HS). This study aimed to determine the influence of laparoscopic or open surgery on the postoperative recovery of colorectal cancer patients having a conventional care (CC) or FT protocol in the postoperative period. Method: A multicentre prospective study was controlled with a retrospective group. The prospective group included 300 patients having elective colorectal resection for cancer. The retrospective control group included 201 patients with the same characteristics who were treated before the introduction of the programme. The patients were divided into four groups including laparoscopy + FT, open surgery + FT, laparoscopy + CC, and open surgery + CC. The primary end-points were HS and morbidity. Secondary end-points included mortality and reoperation rates. Results: The overall median HS was 7 days. The median HS for laparoscopy + FT was 5 days, open + FT 6 days, laparoscopy + CC 9 days and open + CC 10 days (P < 0.001). In the regression model the laparoscopy + FT group had the greatest reduction in HS (P < 0.001). A significant reduction in HS was observed in the laparoscopy + FT group compared with laparoscopy + CC (P < 0.001). The overall patient morbidity was 30.6%. The logistic regression model adjusted for propensity score showed no statistically significant differences between the study groups regarding all other end-points. Conclusion: Colorectal cancer patients who underwent laparoscopic surgery within a multimodal rehabilitation protocol experienced the shortest HS and the lowest morbidity. © 2013 The Association of Coloproctology of Great Britain and Ireland.


PubMed | Hospital Universitario Elche
Type: | Journal: BMC medical genetics | Year: 2011

Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS.The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers.Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients.The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.


The incidence of colorectal cancer (CRC) in Peru has been increasing, and no data have been published on the molecular features. We explored the most relevant genetic events involved in colorectal carcinogenesis, with clinical implications.Using immunohistochemistry for mismatch-repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) and microsatellite instability analysis, we evaluated the status of 90 non-selected CRC Peruvian patients followed in a nationwide reference hospital for cancer (INEN, Lima). Tumours with loss of hMLH1 were evaluated further for hMLH1 promoter hypermethylation and all cases were evaluated for the presence of KRAS and BRAF-V600E mutations.MMR deficiency was found in 35 (38.8%) patients. We identified an unexpected association between MMR deficiency and older age. Among the 14 cases with loss of MLH1, 10 samples exhibited hypermethylation. Of the 90 cases evaluated, 15 (16.7%) carried KRAS mutations; we found one previously unreported mutation (G13R).Peruvian CRC tumours exhibited the highest prevalence of MMR deficiency reported to date. The expected hereditary component was also high. The age of onset of these MMR deficient tumours was greater than that observed for non-MMR deficient cases, suggesting the ineffectiveness of the Bethesda criteria for Lynch syndrome screening in Peru. Prospective studies are warranted to define the molecular characteristics of CRC in this population.

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