Involvement of large rearrangements in MSH6 and PMS2 genes in Southern Italian patients with Lynch syndrome.

Background and aim of the work: The Lynch Syndrome (LS) is associated with germline mutations in one of the MisMatch Repair (MMR) genes. Most of germline mutations are point variants, followed by large rearrangements that account to 15-55% of all pathogenic mutations. Many study reporting the frequency of large rearrangements in the MLH1 and MSH2 genes were performed, while, little is known about the contribution of large rearrangements in other MMR genes, as PMS2 and MSH6. Therefore, in this study we investigated the involvment of large rearrangements in MSH6 and PMS2 genes in a well-characterized series of 20 LS southern Italian patients. Methods: These large rearrangements are not usually detected by methods of mutation analysis, such as denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing, but they are detectable by a known technique as the Multiplex Ligation-Probe Dependent Amplification (MLPA) assay. Results: No large rearrangements were identified in MSH6 gene; instead, a large rearrangement was identified in PMS2 gene. A large duplication including the exons 3 and 4 of the PMS2 gene was identified in a patient who developed a rectum carcinoma at 45 years of age, an endometrial carcinoma and a vaginal cancer at the 65 years of age. Conclusion: We can affirm that the detection of large rearrangements in the MSH6 and PMS2 genes should be included in the routine testing for Lynch syndrome, especially considering the simplicity of the MLPA assay.

[1]  P. Izzo,et al.  Characterization of novel, large duplications in the MSH2 gene of three unrelated Lynch syndrome patients. , 2018, Cancer genetics.

[2]  M. De Rosa,et al.  Same MSH2 Gene Mutation But Variable Phenotypes in 2 Families With Lynch Syndrome: Two Case Reports and Review of Genotype-Phenotype Correlation , 2018, Clinical medicine insights. Case reports.

[3]  J. Bailey-Wilson,et al.  Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge , 2017, Familial Cancer.

[4]  P. Izzo,et al.  Novel Implications in Molecular Diagnosis of Lynch Syndrome , 2017, Gastroenterology research and practice.

[5]  P. Delrio,et al.  The biological complexity of colorectal cancer: insights into biomarkers for early detection and personalized care , 2016, Therapeutic advances in gastroenterology.

[6]  P. Izzo,et al.  Coexistence of MLH3 germline variants in colon cancer patients belonging to families with Lynch syndrome-associated brain tumors , 2016, Journal of Neuro-Oncology.

[7]  M. Nucci,et al.  Peutz-Jeghers Syndrome: Pathobiology, Pathologic Manifestations, and Suggestions for Recommending Genetic Testing in Pathology Reports. , 2016, Surgical pathology clinics.

[8]  E. Harkness,et al.  The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes , 2016, Human mutation.

[9]  P. Peltomäki.  Update on Lynch syndrome genomics , 2016, Familial Cancer.

[10]  P. Izzo,et al.  Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability. , 2015, International journal of molecular medicine.

[11]  P. Delrio,et al.  Genetics, diagnosis and management of colorectal cancer (Review) , 2015, Oncology reports.

[12]  Hiroyuki Yamamoto,et al.  Microsatellite instability: an update , 2015, Archives of Toxicology.

[13]  Michael J. McGuffin,et al.  A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype , 2015, Journal of Medical Genetics.

[14]  Á. Carracedo,et al.  High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families , 2014, Clinical Genetics.

[15]  P. Delrio,et al.  Differential expression of PTEN gene correlates with phenotypic heterogeneity in three cases of patients showing clinical manifestations of PTEN hamartoma tumour syndrome , 2013, Hereditary cancer in clinical practice.

[16]  P. Izzo,et al.  Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion , 2012, BioMed research international.

[17]  M. Baudis,et al.  Improved Multiplex Ligation-Dependent Probe Amplification Analysis Identifies a Deleterious PMS2 Allele Generated by Recombination with Crossover Between PMS2 and PMS2CL , 2012, Genes, chromosomes & cancer.

[18]  M. Grosso,et al.  Association of low‐risk MSH3 and MSH2 variant alleles with Lynch syndrome: Probability of synergistic effects , 2011, International journal of cancer.

[19]  M. Galatola,et al.  Implication of Adenomatous Polyposis Coli and MUTYH Mutations in Familial Colorectal Polyposis , 2009, Diseases of the colon and rectum.

[20]  Matthew D. Dyer,et al.  Human genomic deletions mediated by recombination between Alu elements. , 2006, American journal of human genetics.

[21]  P. Møller,et al.  Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC) , 2005, Genes, chromosomes & cancer.

[22]  A. Iannelli,et al.  Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene , 2000, Oncogene.

[23]  S Srivastava,et al.  A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. , 1998, Cancer research.

[24]  C. Dodaro,et al.  The role of mutation analysis of the APC gene in the management of FAP patients. A controversial issue. , 2016, Annali italiani di chirurgia.

[25]  K. Wimmer,et al.  PMS2 gene mutational analysis: direct cDNA sequencing to circumvent pseudogene interference. , 2014, Methods in molecular biology.

[26]  N. Lindor.  Suspected Hereditary Nonpolyposis Colorectal Cancer: International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) Criteria and Results of Genetic Diagnosis , 1999 .