Genome characteristics of primary carcinomas, local recurrences, carcinomatoses, and liver metastases from colorectal cancer patients

BackgroundColorectal cancer (CRC) is one of the most common causes of cancer-related deaths in the Western world, and despite the fact that metastases are usually the ultimate cause of deaths, the knowledge of the genetics of advanced stages of this disease is limited. In order to identify potential genetic abnormalities underlying the development of local and distant metastases in CRC patients, we have, by comparative genomic hybridization, compared the DNA copy number profiles of 10 primary carcinomas, 14 local recurrences, 7 peritoneal carcinomatoses, and 42 liver metastases from 61 CRC patients.ResultsThe median number of aberrations among the primary carcinomas, local recurrences, carcinomatoses, and liver metastases was 10, 6, 13, and 14, respectively. Several genetic imbalances, such as gains of 7, 8q, 13q, and 20, and losses of 4q, 8p, 17p, and 18, were common in all groups. In contrast, gains of 5p and 12p were more common in the carcinomatoses than in other stages of the disease. With hierarchical cluster analysis, liver metastases could be divided into two main subgroups according to clusters of chromosome changes.ConclusionsEach stage of CRC progression is characterized by a particular genetic profile, and both carcinomatoses and liver metastases are more genetically complex than local recurrences and primary carcinomas. This is the first genome profiling of local recurrences and carcinomatoses, and gains of 5p and 12p seem to be particularly important for the spread of the CRC cells within the peritoneal cavity.

[1]  L. Kunkel,et al.  Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[2]  F. Carey,et al.  The colorectal adenoma–carcinoma sequence , 2002, The British journal of surgery.

[3]  L. Aaltonen,et al.  Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. , 1993, Cancer research.

[4]  S. Leung,et al.  Early-onset colorectal cancer with stable microsatellite DNA and near-diploid chromosomes , 2001, Oncogene.

[5]  H. Scherthan,et al.  Advances in Brief Comparative Genomic in Situ Hybridization of Colon Carcinomas with Replication Error ' , 2006 .

[6]  K. Kinzler,et al.  Clues to the pathogenesis of familial colorectal cancer. , 1993, Science.

[7]  J. Faure,et al.  Peritoneal carcinomatosis from non‐gynecologic malignancies , 2000, Cancer.

[8]  S N Thibodeau,et al.  Microsatellite instability in cancer of the proximal colon. , 1993, Science.

[9]  O. Kronborg,et al.  Karyotypic characterization of colorectal adenocarcinomas , 1995, Genes, chromosomes & cancer.

[10]  R. Lothe,et al.  Assessments of clonal composition of colorectal adenomas by FISH analysis of chromosomes 1, 7, 13 and 20 , 2001, International journal of cancer.

[11]  Heinz Becker,et al.  Gain of chromosome 8q23-24 is a predictive marker for lymph node positivity in colorectal cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[12]  F. Al-Mulla,et al.  Comparative genomic hybridization analysis of primary colorectal carcinomas and their synchronous metastases , 1999, Genes, chromosomes & cancer.

[13]  O. Haas,et al.  Felix Mitelman: Database of chromosome aberrations in cancer , 2002, Human Genetics.

[14]  J W Arends,et al.  Molecular interactions in the Vogelstein model of colorectal carcinoma , 2000, The Journal of pathology.

[15]  T. Stokke,et al.  Prognostic significance of recurrent chromosomal aberrations detected by comparative genomic hybridization in sporadic colorectal cancer , 2001, International Journal of Colorectal Disease.

[16]  Y. Nakamura,et al.  Genetic alterations during colorectal-tumor development. , 1988, The New England journal of medicine.

[17]  B Johansson,et al.  Chromosomal imbalance maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms. , 1997, Cancer research.

[18]  S. Hamilton,et al.  Cytogenetic analysis of intestinal polyps in polyposis syndromes: comparison with sporadic colorectal adenomas. , 1993, Cancer genetics and cytogenetics.

[19]  A. Wyllie,et al.  Heterogeneity studies identify a subset of sporadic colorectal cancers without evidence for chromosomal or microsatellite instability , 1999, Oncogene.

[20]  Inge Jonassen,et al.  J-Express: exploring gene expression data using Java , 2001, Bioinform..

[21]  R. Kolodner,et al.  Identification of mismatch repair genes and their role in the development of cancer. , 1995, Current opinion in genetics & development.

[22]  Iscn.  International System for Human Cytogenetic Nomenclature , 1978 .

[23]  J. Arends,et al.  Colorectal adenoma to carcinoma progression follows multiple pathways of chromosomal instability. , 2002, Gastroenterology.

[24]  R S Warren,et al.  Chromosome arm 20q gains and other genomic alterations in colorectal cancer metastatic to liver, as analyzed by comparative genomic hybridization and fluorescence in situ hybridization , 1999, Genes, chromosomes & cancer.

[25]  T. Stephenson,et al.  Analysis of colorectal tumor progression by microdissection and comparative genomic hybridization , 2003, Genes, chromosomes & cancer.

[26]  M. Kusano,et al.  Genetic Changes in Primary Colorectal Cancer by Comparative Genomic Hybridization , 1998, Surgery Today.

[27]  A. Walch,et al.  Distinct chromosomal imbalances in nonpolypoid and polypoid colorectal adenomas indicate different genetic pathways in the development of colorectal neoplasms. , 2003, The American journal of pathology.

[28]  D. Albertson,et al.  Chromosome aberrations in solid tumors , 2003, Nature Genetics.

[29]  D. Schaid,et al.  Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. , 1999, Journal of the National Cancer Institute.

[30]  Keith Wilson,et al.  Silence of chromosomal amplifications in colon cancer. , 2002, Cancer research.

[31]  F. Mitelman.  ISCN 1995 : an international system for human cytogenetic nomenclature (1995) : recommendations of the International Standing Committee on Human Cytogenetic Nomenclature : Memphis, Tennessee, USA, October 9-13, 1994 , 1995 .

[32]  S. Petersen,et al.  Incidence of chromosomal imbalances in advanced colorectal carcinomas and their metastases , 2002, Virchows Archiv.

[33]  H. McLeod,et al.  Tumour markers of prognosis in colorectal cancer , 1999, British Journal of Cancer.

[34]  J. Inazawa,et al.  Chromosomal aberrations in colorectal cancers and liver metastases analyzed by comparative genomic hybridization , 2001, International journal of cancer.

[35]  Thomas Ried,et al.  Comparative genomic hybridization reveals a specific pattern of chromosomal gains and losses during the genesis of colorectal tumors , 1996, Genes, chromosomes & cancer.

[36]  N. Kemeny,et al.  Surgical Debulking and Intraperitoneal Chemotherapy for Established Peritoneal Metastases From Colon and Appendix Cancer , 2001, Annals of Surgical Oncology.

[37]  T. Yeatman,et al.  Analysis of colorectal cancer by comparative genomic hybridization: evidence for induction of the metastatic phenotype by loss of tumor suppressor genes. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[38]  B. Dutrillaux,et al.  Cytogenetics of colorectal adenocarcinomas. , 1990, Cancer genetics and cytogenetics.

[39]  R. Lothe,et al.  Allelotype profiles of local recurrences and distant metastases from colorectal‐cancer patients , 1996, International journal of cancer.

[40]  B. Vogelstein,et al.  A genetic model for colorectal tumorigenesis , 1990, Cell.

[41]  M. Kusano,et al.  Genetic changes in colorectal carcinoma tumors with liver metastases analyzed by comparative genomic hybridization and DNA ploidy , 2001, Cancer.

[42]  D. Pinkel,et al.  Comparative Genomic Hybridization for Molecular Cytogenetic Analysis of Solid Tumors , 2022 .

[43]  H. McLeod,et al.  Comparative genomic hybridization and chromosomal instability in solid tumours , 1999, British Journal of Cancer.

[44]  K. Kinzler,et al.  Genetic instability in colorectal cancers , 1997, Nature.

[45]  C. Lillingston.  CANCER IN NORWAY , 1960 .

[46]  S. Leung,et al.  Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation , 2000, Oncogene.

[47]  R. Lothe,et al.  DNA copy number changes in malignant ovarian germ cell tumors. , 2000, Cancer research.

[48]  Darryl Shibata,et al.  Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis , 1993, Nature.

[49]  J. Coxhead,et al.  Mutations in APC, Kirsten-ras, and p53—alternative genetic pathways to colorectal cancer , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[50]  X. Guan,et al.  Recurrent genetic alterations in 26 colorectal carcinomas and 21 adenomas from Chinese patients. , 2003, Cancer genetics and cytogenetics.

[51]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[52]  E. Fearon,et al.  DCC: linking tumor suppressor genes and altered cell surface interactions in cancer? , 1995, Current opinion in genetics & development.

[53]  T. Stokke,et al.  Chromosomal gains and losses in primary colorectal carcinomas detected by CGH and their associations with tumour DNA ploidy, genotypes and phenotypes , 1999, British Journal of Cancer.

[54]  P. V. van Diest,et al.  Progression from colorectal adenoma to carcinoma is associated with non-random chromosomal gains as detected by comparative genomic hybridisation. , 1998, Journal of clinical pathology.

[55]  R. Lothe,et al.  Genetic profiling of colorectal cancer liver metastases by combined comparative genomic hybridization and G‐banding analysis , 2003, Genes, chromosomes & cancer.

[56]  F. Waldman,et al.  Chromosomal alterations in ulcerative colitis-related and sporadic colorectal cancers by comparative genomic hybridization. , 2000, Human pathology.