Target gene mutational pattern in Lynch syndrome colorectal carcinomas according to tumour location and germline mutation

Background:We previously reported that the target genes in sporadic mismatch repair (MMR)-deficient colorectal carcinomas (CRCs) in the distal colon differ from those occurring elsewhere in the colon. This study aimed to compare the target gene mutational pattern in microsatellite instability (MSI) CRC from Lynch syndrome patients stratified by tumour location and germline mutation, as well as with that of sporadic disease.Methods:A series of CRC from Lynch syndrome patients was analysed for MSI in genes predicted to be selective MSI targets and known to be involved in several pathways of colorectal carcinogenesis.Results:The most frequently mutated genes belong to the TGF-β superfamily pathway, namely ACVR2A and TGFBR2. A significantly higher frequency of target gene mutations was observed in CRC from patients with germline mutations in MLH1 or MSH2 when compared with MSH6. Mutations in microsatellite sequences (A)7 of BMPR2 and (A)8 of MSH3 were significantly more frequent in the distal CRC. Additionally, we observed differences in MSH3 and TGFBR2 mutational frequency between Lynch syndrome and sporadic MSI CRC regarding tumour location.Conclusions:Our results indicate that the pattern of genetic changes differs in CRC depending on tumour location and between Lynch syndrome and sporadic MSI CRC, suggesting that carcinogenesis can occur by different pathways even if driven by generalised MSI.

[1]  C. Capella,et al.  MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers , 2012, Clinical Cancer Research.

[2]  M. Perucho,et al.  Microsatellite instability: The mutator that mutates the other mutator , 1996, Nature Medicine.

[3]  T. Iwama,et al.  Frequent mutation of beta-catenin and APC genes in primary colorectal tumors from patients with hereditary nonpolyposis colorectal cancer. , 1999, Cancer research.

[4]  H. Hollema,et al.  Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. , 1999, American journal of human genetics.

[5]  T. Iwama,et al.  Alterations of repeated sequences in 5′ upstream and coding regions in colorectal tumors from patients with hereditary nonpolyposis colorectal cancer and Turcot syndrome , 2001, Oncogene.

[6]  G. Thomas,et al.  Frequent frameshift mutations of the TCF-4 gene in colorectal cancers with microsatellite instability. , 1999, Cancer research.

[7]  P. Peltomäki,et al.  Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability. , 2002, The American journal of pathology.

[8]  T. Iwama,et al.  Frequent Mutation of β-Catenin and APC Genes in Primary Colorectal Tumors from Patients with Hereditary Nonpolyposis Colorectal Cancer , 1999 .

[9]  H. Yamamoto,et al.  Somatic frameshift mutations in DNA mismatch repair and proapoptosis genes in hereditary nonpolyposis colorectal cancer. , 1998, Cancer research.

[10]  G. Fleuren,et al.  HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression , 2007, BMC Cancer.

[11]  J. Jiricny,et al.  Familial colorectal cancer: eleven years of data from a registry program in Switzerland , 2011, Familial Cancer.

[12]  R. Lothe,et al.  Genetic and epigenetic changes of components affecting the WNT pathway in colorectal carcinomas stratified by microsatellite instability. , 2005, Neoplasia.

[13]  A. de la Chapelle,et al.  Hereditary Colorectal Cancer , 2010 .

[14]  J. Jass.  Classification of colorectal cancer based on correlation of clinical, morphological and molecular features , 2007, Histopathology.

[15]  S. Schwartz,et al.  Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation , 2004, Genes, chromosomes & cancer.

[16]  H T Lynch,et al.  New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. , 1999, Gastroenterology.

[17]  T. Frebourg,et al.  Genetic variations of the A13/A14 repeat located within the EGFR 3′ untranslated region have no oncogenic effect in patients with colorectal cancer , 2013, BMC Cancer.

[18]  N. Yoo,et al.  Somatic frameshift mutations of bone morphogenic protein receptor 2 gene in gastric and colorectal cancers with microsatellite instability , 2010, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[19]  A. Rashid,et al.  Somatic deletions of the polyA tract in the 3' untranslated region of epidermal growth factor receptor are common in microsatellite instability-high endometrial and colorectal carcinomas. , 2012, Archives of pathology & laboratory medicine.

[20]  Mitochondrial genome alterations in rectal and sigmoid carcinomas. , 2009, Cancer letters.

[21]  Peter Beighton,et al.  de la Chapelle, A. , 1997 .

[22]  L. Aaltonen,et al.  Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. , 1998, The New England journal of medicine.

[23]  Kathleen R. Cho,et al.  A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. , 1995, Cancer research.

[24]  Y. Yuasa,et al.  Mutations of the transforming growth factor-beta type II receptor gene and genomic instability in hereditary nonpolyposis colorectal cancer. , 1995, Biochemical and biophysical research communications.

[25]  H. Olsson,et al.  Somatic frameshift alterations in mononucleotide repeat‐containing genes in different tumor types from an HNPCC family with germline MSH2 mutation , 2000, Genes, chromosomes & cancer.

[26]  S. Farrington,et al.  The MSH2 c.388_389del mutation shows a founder effect in Portuguese Lynch syndrome families , 2013, Clinical genetics.

[27]  R. Lothe,et al.  Colorectal carcinomas with microsatellite instability display a different pattern of target gene mutations according to large bowel site of origin , 2010, BMC Cancer.

[28]  Sudhir Srivastava,et al.  Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. , 2004, Journal of the National Cancer Institute.

[29]  Y. Yuasa,et al.  Frequent somatic mutations of hMSH3 with reference to microsatellite instability in hereditary nonpolyposis colorectal cancers. , 1997, Biochemical and biophysical research communications.

[30]  K. Kinzler,et al.  Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. , 2007, Journal of the National Cancer Institute.

[31]  J. Rüschoff,et al.  T-cell factor-4 frameshift mutations occur frequently in human microsatellite instability-high colorectal carcinomas but do not contribute to carcinogenesis. , 2002, Cancer research.

[32]  B. Vogelstein,et al.  Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences. , 1998, The American journal of pathology.

[33]  Heather Hampel,et al.  Feasibility of screening for Lynch syndrome among patients with colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  H T Lynch,et al.  Hereditary Nonpolyposis Colorectal Cancer Patients Replication Errors in Benign and Malignant Tumors from , 2006 .

[35]  D. Hommes,et al.  The bone morphogenetic protein pathway is inactivated in the majority of sporadic colorectal cancers. , 2008, Gastroenterology.

[36]  N. Matsubara,et al.  E2F-4 mutation in hereditary non-polyposis colorectal cancer. , 2002, Journal of experimental & clinical cancer research : CR.

[37]  R. Henrique,et al.  A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families , 2011, Genetics in Medicine.