Publications by authors named "Eva Hernández-Illán"

16 Publications

  • Page 1 of 1

Increased Th17-Related Cytokine Serum Levels in Patients With Multiple Polyps of Unexplained Origin.

Clin Transl Gastroenterol 2020 03;11(3):e00143

Laboratorio de Investigación, Hospital General Universitario de Alicante, Instituto de Investigación sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain.

Objectives: Most patients with multiple colonic polyps do not have a known genetic or hereditary origin. Our aim was to analyze the presence of inflammatory cytokines and levels of glucose, insulin, and C-reactive protein (CRP) in patients with multiple colonic polyps.

Methods: Eighty-three patients with 10 or more adenomatous or serrated polyps and 53 control people with normal colonoscopy were included. Smoking habits were registered, and glucose, CRP, and basal insulin in the serum/blood were measured. Quantification of IL-2, IL-4, IL-6, IL-10, IL-11, IL-17A, and IL-23 cytokine levels in the serum was performed by a high-sensitivity enzyme-linked immunosorbent assay.

Results: Smoking and diabetes were more prevalent in those with colonic polyps than in the control people (67% vs 16%, P = 0.001; 11% vs 2%, P = 0.048). In addition, the cytokine serum levels were higher, i.e., IL-2 (P = 0.001), IL-4 (P = 0.001), IL-6 (P = 0.001), IL-17A (P = 0.001), IL-23 (P = 0.014), and CRP (P = 0.003). Adjusting for sex, smoking, and diabetes in a multivariate analysis, IL-2, IL-4, IL-6, IL-17A, and IL-23 remained independently elevated in cases with multiple polyps.

Discussion: These results indicate that immune responses mediated by Th17 cells may be involved in the pathogenesis of multiple colonic polyps.
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http://dx.doi.org/10.14309/ctg.0000000000000143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145049PMC
March 2020

CNApp, a tool for the quantification of copy number alterations and integrative analysis revealing clinical implications.

Elife 2020 Jan 15;9. Epub 2020 Jan 15.

Gastrointestinal and Pancreatic Oncology Team, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universitat de Barcelona, Barcelona, Spain.

Somatic copy number alterations (CNAs) are a hallmark of cancer, but their role in tumorigenesis and clinical relevance remain largely unclear. Here, we developed CNApp, a web-based tool that allows a comprehensive exploration of CNAs by using purity-corrected segmented data from multiple genomic platforms. CNApp generates genome-wide profiles, computes CNA scores for broad, focal and global CNA burdens, and uses machine learning-based predictions to classify samples. We applied CNApp to the TCGA pan-cancer dataset of 10,635 genomes showing that CNAs classify cancer types according to their tissue-of-origin, and that each cancer type shows specific ranges of broad and focal CNA scores. Moreover, CNApp reproduces recurrent CNAs in hepatocellular carcinoma and predicts colon cancer molecular subtypes and microsatellite instability based on broad CNA scores and discrete genomic imbalances. In summary, CNApp facilitates CNA-driven research by providing a unique framework to identify relevant clinical implications. CNApp is hosted at https://tools.idibaps.org/CNApp/.
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http://dx.doi.org/10.7554/eLife.50267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010409PMC
January 2020

Epigenetics of colorectal cancer: biomarker and therapeutic potential.

Nat Rev Gastroenterol Hepatol 2020 02 3;17(2):111-130. Epub 2020 Jan 3.

Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.

Colorectal cancer (CRC), a leading cause of cancer-related death worldwide, evolves as a result of the stepwise accumulation of a series of genetic and epigenetic alterations in the normal colonic epithelium, leading to the development of colorectal adenomas and invasive adenocarcinomas. Although genetic alterations have a major role in a subset of CRCs, the pathophysiological contribution of epigenetic aberrations in this malignancy has attracted considerable attention. Data from the past couple of decades has unequivocally illustrated that epigenetic marks are important molecular hallmarks of cancer, as they occur very early in disease pathogenesis, involve virtually all key cancer-associated pathways and, most importantly, can be exploited as clinically relevant disease biomarkers for diagnosis, prognostication and prediction of treatment response. In this Review, we summarize the current knowledge on the best-studied epigenetic modifications in CRC, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators. We focus on the emerging potential for the bench-to-bedside translation of some of these epigenetic alterations into clinical practice and discuss the burgeoning evidence supporting the potential of emerging epigenetic therapies in CRC as we usher in the era of precision medicine.
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http://dx.doi.org/10.1038/s41575-019-0230-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228650PMC
February 2020

Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability and CIMP status: Prognostic implications and response to chemotherapy.

PLoS One 2018 6;13(9):e0203051. Epub 2018 Sep 6.

Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain.

Objective: The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype's response to chemotherapy.

Design: This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS).

Results: Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P<0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P<0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005).

Conclusion: We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203051PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126803PMC
February 2019

Mutational Signatures in Cancer (MuSiCa): a web application to implement mutational signatures analysis in cancer samples.

BMC Bioinformatics 2018 06 14;19(1):224. Epub 2018 Jun 14.

Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD, University of Barcelona, Barcelona, Spain.

Background: Mutational signatures have been proved as a valuable pattern in somatic genomics, mainly regarding cancer, with a potential application as a biomarker in clinical practice. Up to now, several bioinformatic packages to address this topic have been developed in different languages/platforms. MutationalPatterns has arisen as the most efficient tool for the comparison with the signatures currently reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. However, the analysis of mutational signatures is nowadays restricted to a small community of bioinformatic experts.

Results: In this work we present Mutational Signatures in Cancer (MuSiCa), a new web tool based on MutationalPatterns and built using the Shiny framework in R language. By means of a simple interface suited to non-specialized researchers, it provides a comprehensive analysis of the somatic mutational status of the supplied cancer samples. It permits characterizing the profile and burden of mutations, as well as quantifying COSMIC-reported mutational signatures. It also allows classifying samples according to the above signature contributions.

Conclusions: MuSiCa is a helpful web application to characterize mutational signatures in cancer samples. It is accessible online at http://bioinfo.ciberehd.org/GPtoCRC/en/tools.html and source code is freely available at https://github.com/marcos-diazg/musica .
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http://dx.doi.org/10.1186/s12859-018-2234-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001047PMC
June 2018

Methylation and Expression Status Does Not Predict Response to 5-FU-based Chemotherapy in Colorectal Cancer.

Clin Cancer Res 2018 06 13;24(12):2820-2827. Epub 2018 Mar 13.

Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.

A recent study reported that 5-fluorouracil (5-FU)-based chemotherapy is less effective in treating patients with advanced colorectal cancer demonstrating hypermethylation of the gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts. Two cohorts of 783 patients with colorectal cancer: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of methylation and expression as a predictor of response of colorectal cancer patients to 5-FU-based chemotherapy. DNA methylation status of the gene in patients with colorectal cancer was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed. Correlation between TFAP2E methylation status and IHC staining was performed in 607 colorectal cancer samples. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by hypermethylation in stage IV patients [HR, 1.21; 95% confidence interval (CI), 0.79-1.87; log-rank = 0.6]. In stage II-III cases, disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU-treated (HR, 0.91; 95% CI, 0.52-1.59; log-rank = 0.9) as well as in nontreated patients (HR, 0.88; 95% CI, 0.5-1.54; log-rank = 0.7). hypermethylation does not correlate with loss of its protein expression. Our large, systematic, and comprehensive study indicates that methylation and expression may not play a major role in predicting response to 5-FU-based chemotherapy in patients with colorectal cancer. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396148PMC
June 2018

KRAS and BRAF somatic mutations in colonic polyps and the risk of metachronous neoplasia.

PLoS One 2017 27;12(9):e0184937. Epub 2017 Sep 27.

Service of Digestive Medicine, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain.

Background & Aims: High-risk features of colonic polyps are based on size, number, and pathologic characteristics. Surveillance colonoscopy is often recommended according to these findings. This study aimed to determine whether the molecular characteristics of polyps might provide information about the risk of metachronous advanced neoplasia.

Methodology: We retrospectively included 308 patients with colonic polyps. A total of 995 polyps were collected and tested for somatic BRAF and KRAS mutations. Patients were classified into 3 subgroups, based on the polyp mutational profile at baseline, as follows: non-mutated polyps (Wild-type), at least one BRAF-mutated polyp, or at least one KRAS-mutated polyp. At surveillance, advanced adenomas were defined as adenomas ≥ 10 mm and/or with high grade dysplasia or a villous component. In contrast, advanced serrated polyps were defined as serrated polyps ≥ 10 mm in any location, located proximal to the splenic flexure with any size or with dysplasia.

Results: At baseline, 289 patients could be classified as wild-type (62.3%), BRAF mutated (14.9%), or KRAS mutated (22.8%). In the univariate analysis, KRAS mutations were associated with the development of metachronous advanced polyps (OR: 2.36, 95% CI: 1.22-4.58; P = 0.011), and specifically, advanced adenomas (OR: 2.42, 95% CI: 1.13-5.21; P = 0.023). The multivariate analysis, adjusted for age and sex, also showed associations with the development of metachronous advanced polyps (OR: 2.27, 95% CI: 1.15-4.46) and advanced adenomas (OR: 2.23, 95% CI: 1.02-4.85).

Conclusions: Our results suggested that somatic KRAS mutations in polyps represent a potential molecular marker for the risk of developing advanced neoplasia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184937PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617162PMC
October 2017

Increased Risk of Colorectal Cancer in Patients With Multiple Serrated Polyps and Their First-Degree Relatives.

Gastroenterology 2017 07 9;153(1):106-112.e2. Epub 2017 Apr 9.

Research Laboratory, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research Instituto de Investigación Sanitaria y Biomédica de Alicante, Alicante, Spain; Service of Digestive Medicine, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research Instituto de Investigación Sanitaria y Biomédica de Alicante, Alicante, Spain. Electronic address:

Background & Aims: We investigated whether patients with multiple serrated polyps, but not meeting the World Health Organization criteria for serrated polyposis syndrome, and their relatives have similar risks for colorectal cancer (CRC) as those diagnosed with serrated polyposis.

Methods: We collected data from patients with more than 10 colonic polyps, recruited in 2008-2009 from 24 hospitals in Spain for a study of causes of multiple colonic polyps. We analyzed data from 53 patients who met the criteria for serrated polyposis and 145 patients who did not meet these criteria, but who had more than 10 polyps throughout the colon, of which more than 50% were serrated. We calculated age- and sex-adjusted standardized incidence ratios (SIRs) for CRC in both groups, as well as in their first-degree relatives.

Results: The prevalence of CRC was similar between patients with confirmed serrated polyposis and multiple serrated polyps (odds ratio, 1.35; 95% confidence interval [CI], 0.64-2.82; P = .40). The SIR for CRC in patients with serrated polyposis (0.51; 95% CI, 0.01-2.82) did not differ significantly from the SIR for CRC in patients with multiple serrated polyps (0.74; 95% CI, 0.20-1.90; P = .70). The SIR for CRC also did not differ significantly between first-degree relatives of these groups (serrated polyposis: 3.28, 95% CI, 2.16-4.77; multiple serrated polyps: 2.79, 95% CI, 2.10-3.63; P = .50). Kaplan-Meier analysis showed no differences in the incidence of CRC between groups during the follow-up period (log-rank, 0.6).

Conclusions: The risk of CRC in patients with multiple serrated polyps who do not meet the criteria for serrated polyposis, and in their first-degree relatives, is similar to that of patients diagnosed with serrated polyposis.
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http://dx.doi.org/10.1053/j.gastro.2017.04.003DOI Listing
July 2017

Streptococcus gallolyticus infection in colorectal cancer and association with biological and clinical factors.

PLoS One 2017 29;12(3):e0174305. Epub 2017 Mar 29.

Instituto de Investigación Sanitaria y Biómedica de Alicante (ISABIAL)-FISABIO, Alicante, Spain.

There is an unambiguous association of Streptococcus gallolyticus infection with colorectal cancer, although there is limited information about epidemiology or interaction between molecular and environmental factors. We performed an original quantitative analysis of S. gallolyticus in unselected colorectal cancer patients (n = 190) and their association with clinical, pathological tumor molecular profiles (microsatellite instability, hypermethylator phenotype and chromosomal instability pathways), and other biological factors in colorectal tumor and normal tissues (cytomegalovirus and Epstein-Barr virus infection). We developed a new quantitative method to assess bacterial load. Analytical validation was reached with a very high sensitivity and specificity. Our results showed a 3.2% prevalence of S. gallolyticus infection in our unselected cohort of colorectal cancer cases (6/190). The average S. gallolyticus copy number was 7,018 (range 44-34,585). No previous reports relating to S. gallolyticus infection have been published for unselected cohorts of patients. Finally, and despite a low prevalence of S. gallolyticus in this study, we were able to define a specific association with tumor tissue (p = 0.03) and with coinfection with Epstein-Barr virus (p = 0.042; OR: 9.49; 95% IC: 1.1-82.9). The prevalence data provided will be very useful in the design of future studies, and will make it possible to estimate the sample size needed to assess precise objectives. In conclusion, our results show a low prevalence of S. gallolyticus infection in unselected colorectal cancer patients and an association of positive S. gallolyticus infection with tumor tissue and Epstein-Barr virus coinfection. Further studies will be needed to definitively assess the prevalence of S. gallolyticus in colorectal cancer and the associated clinicopathological and molecular profiles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174305PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371321PMC
August 2017

Characterization of a novel POLD1 missense founder mutation in a Spanish population.

J Gene Med 2017 Apr;19(4)

Unidad Genética Molecular, Hospital Universitario Elche, Elche, Spain.

Background: We identified a new and a recurrent POLD1 mutation associated with predisposition to colorectal cancer (CRC). We characterized the molecular and clinical nature of the potential POLD1 founder mutation in families from Valencia (Spain).

Methods: Clinical and molecular data were collected from four independent families known to have a POLD1 Leu474Pro mutation. To establish its founder effect, haplotype construction was performed using 14 flanking POLD1 polymorphic markers. We calculated penetrance estimates and clinical expressivity, globally and stratified by age and sex.

Results: We included 32 individuals from the four families: 20 carriers and 12 noncarriers. A common haplotype was identified in these families in a region comprising 2,995 Mb, confirming L474P as the first founder POLD1 mutation identified. Thirteen tumors diagnosed in 10 POLD1 carriers: eight CRC, three endometrial and two other tumors were considered. The median age of cancer onset for POLD1 mutation carriers was 48 years. The observed penetrance was 50% and the cumulative risk at age of 50 years was 30%.

Conclusions: The findings of the present study contribute to a better understanding of CRC genetics in the Spanish population. The clinical phenotype for this mutation is similar to that in Lynch syndrome. Future studies using next generation sequencing with large gene panels for any hereditary cancer condition will offer the possibility of detecting POLE/POLD1 mutations in unsuspected clinical situations, demonstrating a more real and unbiased picture of the associated phenotype.
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http://dx.doi.org/10.1002/jgm.2951DOI Listing
April 2017

Serrated colorectal cancer: Molecular classification, prognosis, and response to chemotherapy.

World J Gastroenterol 2016 Apr;22(13):3516-30

Oscar Murcia, Miriam Juárez, Eva Hernández-Illán, Cecilia Egoavil, Mar Giner-Calabuig, María Rodríguez-Soler, Rodrigo Jover, Unidad de Gastroenterología, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria Isabial, 03010 Alicante, Spain.

Molecular advances support the existence of an alternative pathway of colorectal carcinogenesis that is based on the hypermethylation of specific DNA regions that silences tumor suppressor genes. This alternative pathway has been called the serrated pathway due to the serrated appearance of tumors in histological analysis. New classifications for colorectal cancer (CRC) were proposed recently based on genetic profiles that show four types of molecular alterations: BRAF gene mutations, KRAS gene mutations, microsatellite instability, and hypermethylation of CpG islands. This review summarizes what is known about the serrated pathway of CRC, including CRC molecular and clinical features, prognosis, and response to chemotherapy.
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http://dx.doi.org/10.3748/wjg.v22.i13.3516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814638PMC
April 2016

The heritability and patterns of DNA methylation in normal human colorectum.

Hum Mol Genet 2016 06 2;25(12):2600-2611. Epub 2016 Mar 2.

The Roslin Institute, The University of Edinburgh, Edinburgh, EH25 9RG, UK,

DNA methylation (DNAm) has been linked to changes in chromatin structure, gene expression and disease. The DNAm level can be affected by genetic variation; although, how this differs by CpG dinucleotide density and genic location of the DNAm site is not well understood. Moreover, the effect of disease causing variants on the DNAm level in a tissue relevant to disease has yet to be fully elucidated. To this end, we investigated the phenotypic profiles, genetic effects and regional genomic heritability for 196080 DNAm sites in healthy colorectum tissue from 132 unrelated Colombian individuals. DNAm sites in regions of low-CpG density were more variable, on average more methylated and were more likely to be significantly heritable when compared with DNAm sites in regions of high-CpG density. DNAm sites located in intergenic regions had a higher mean DNAm level and were more likely to be heritable when compared with DNAm sites in the transcription start site (TSS) of a gene expressed in colon tissue. Within CpG-dense regions, the propensity of the DNAm level to be heritable was lower in the TSS of genes expressed in colon tissue than in the TSS of genes not expressed in colon tissue. In addition, regional genetic variation was associated with variation in local DNAm level no more frequently for DNAm sites within colorectal cancer risk regions than it was for DNAm sites outside such regions. Overall, DNAm sites located in different genomic contexts exhibited distinguishable profiles and may have a different biological function.
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http://dx.doi.org/10.1093/hmg/ddw072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181623PMC
June 2016

Prevalence of MLH1 constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer.

J Med Genet 2015 Jul 23;52(7):498-502. Epub 2015 Apr 23.

Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.

Background: The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC).

Methods: Patients with diagnoses of CRC (n=2123) were included in the unselected group. For comparison, a group of 847 selected patients with CRC who fulfilled the revised Bethesda guidelines (rBG) were also included. Somatic and constitutional MLH1 methylation was assayed via methylation-specific multiplex ligation-dependent probe amplification of cases lacking MLH1 expression. Germline alterations in mismatch-repair (MMR) genes were assessed via Sanger sequencing and methylation-specific multiplex ligation-dependent probe amplification.

Results: Loss of MLH1 expression occurred in 5.5% of the unselected series and 12.5% of the selected series (p<0.0001). No constitutional epimutations in MLH1 were detected in the unselected population (0/62); five cases from the selected series were positive for MLH1 epimutations (15.6%, 5/32; p=0.004).

Conclusions: Our results suggest a negligible prevalence of MLH1 constitutional epimutations in unselected cases of CRC. Therefore, MLH1 constitutional epimutation analysis should be conducted only for patients who fulfil the rBG and who lack MLH1 expression with methylated MLH1.
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http://dx.doi.org/10.1136/jmedgenet-2015-103076DOI Listing
July 2015

Prevalence of germline MUTYH mutations among Lynch-like syndrome patients.

Eur J Cancer 2014 Sep 18;50(13):2241-50. Epub 2014 Jun 18.

Molecular Genetics Laboratory, Elche University Hospital, Elche, Alicante, Spain. Electronic address:

Background And Aims: Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients.

Methods: Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed.

Results: We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P=0.02) and wildtype patients (P<0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P<0.0001).

Conclusions: A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.
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http://dx.doi.org/10.1016/j.ejca.2014.05.022DOI Listing
September 2014

New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.

Hum Mol Genet 2014 Jul 5;23(13):3506-12. Epub 2014 Feb 5.

Hereditary Cancer Program and.

Germline mutations in DNA polymerase ɛ (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onset CRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T>C (p.Leu474Pro), was identified in a mismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays. POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered.
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http://dx.doi.org/10.1093/hmg/ddu058DOI Listing
July 2014

TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.

PLoS One 2012 23;7(1):e30812. Epub 2012 Jan 23.

Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.

In colorectal cancer (CRC), an inherited susceptibility risk affects about 35% of patients, whereas high-penetrance germline mutations account for <6% of cases. A considerable proportion of sporadic tumors could be explained by the coinheritance of multiple low-penetrance variants, some of which are common. We assessed the susceptibility to CRC conferred by genetic variants at the TGFBR1 locus. We analyzed 14 polymorphisms and the allele-specific expression (ASE) of TGFBR1 in 1025 individuals from the Spanish population. A case-control study was undertaken with 504 controls and 521 patients with sporadic CRC. Fourteen polymorphisms located at the TGFBR1 locus were genotyped with the iPLEX Gold (MassARRAY-Sequenom) technology. Descriptive analyses of the polymorphisms and haplotypes and association studies were performed with the SNPator workpackage. No relevant associations were detected between individual polymorphisms or haplotypes and the risk of CRC. The TGFBR1*9A/6A polymorphism was used for the ASE analysis. Heterozygous individuals were analyzed for ASE by fragment analysis using cDNA from normal tissue. The relative level of allelic expression was extrapolated from a standard curve. The cutoff value was calculated with Youden's index. ASE was found in 25.4% of patients and 16.4% of controls. Considering both bimodal and continuous types of distribution, no significant differences between the ASE values of patients and controls were identified. Interestingly, a combined analysis of the polymorphisms and ASE for the association with CRC occurrence revealed that ASE-positive individuals carrying one of the most common haplotypes (H2: 20.7%) showed remarkable susceptibility to CRC (RR: 5.25; 95% CI: 2.547-5.250; p<0.001) with a synergy factor of 3.7. In our study, 54.1% of sporadic CRC cases were attributable to the coinheritance of the H2 haplotype and TGFBR1 ASE. These results support the hypothesis that the allelic architecture of cancer genes, rather than individual polymorphisms, more accurately defines the CRC risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030812PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264637PMC
June 2012