Accumulated Clonal Genetic Alterations in Familial and Sporadic Colorectal Carcinomas with Widespread Instability in Microsatellite Sequences
| Autor: | Takato Fujiwara, Patti A. Longo, Susan V. Booker, Joshua M. Stolker, Jeremy R. Jass, James R. Eshleman, Asif Rashid, Toshiaki Watanabe, Jin Jen, Jane Green, Bert Vogelstein, Hoguen Kim, Henry T. Lynch, Stanley R. Hamilton |
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| Rok vydání: | 1998 |
| Předmět: |
Male
DNA Mutational Analysis Cell Cycle Proteins Gene mutation medicine.disease_cause Proto-Oncogene Mas Germline Transforming Growth Factor beta bcl-2-Associated X Protein Aged 80 and over Mutation Nuclear Proteins DNA Neoplasm Middle Aged Adenocarcinoma Mucinous Neoplasm Proteins DNA-Binding Proteins MutS Homolog 2 Protein Proto-Oncogene Proteins c-bcl-2 Female Colorectal Neoplasms MutL Protein Homolog 1 Transcription Factor DP1 Adult Genes APC E2F4 Transcription Factor Biology Pathology and Forensic Medicine Frameshift mutation Proto-Oncogene Proteins p21(ras) Proto-Oncogene Proteins medicine Humans Point Mutation Adaptor Proteins Signal Transducing Aged Genetic heterogeneity Point mutation Microsatellite instability medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis Molecular biology digestive system diseases E2F Transcription Factors Tumor Suppressor Protein p53 Carrier Proteins Chromosomes Human Pair 18 Carcinogenesis Microsatellite Repeats Retinoblastoma-Binding Protein 1 Transcription Factors Regular Articles |
| Zdroj: | The American Journal of Pathology. 153:1063-1078 |
| ISSN: | 0002-9440 |
| Popis: | A subset of hereditary and sporadic colorectal carcinomas is defined by microsatellite instability (MSI), but the spectra of gene mutations have not been characterized extensively. Thirty-nine hereditary nonpolyposis colorectal cancer syndrome carcinomas (HNPCCa) and 57 sporadic right-sided colonic carcinomas (SRSCCa) were evaluated. Of HNPCCa, 95% (37/39) were MSI-positive as contrasted with 31% (18/57) of SRSCCa (P0.000001), but instability tended to be more widespread in SRSCCa (P = 0.08). Absence of nuclear hMSH2 mismatch repair gene product by immunohistochemistry was associated with germline hMSH2 mutation (P = 0.0007). The prevalence of K-ras proto-oncogene mutations was similar in HNPCCa and SRSCCa (30% (11/37) and 30% (16/54)), but no HNPCCa from patients with germline hMSH2 mutation had codon 13 mutation (P = 0.02), and two other HNPCCa had multiple K-ras mutations attributable to subclones. 18q allelic deletion and p53 gene product overexpression were inversely related to MSI (P = 0.0004 and P = 0.0001, respectively). Frameshift mutation of the transforming growth factor beta type II receptor gene was frequent in all MSI-positive cancers (85%, 46/54), but mutation of the E2F-4 transcription factor gene was more common in HNPCCa of patients with germline hMSH2 mutation than in those with germline bMLH1 mutation (100% (8/8) versus 40% (2/5), P = 0.04), and mutation of the Bax proapoptotic gene was more frequent in HNPCCa than in MSI-positive SRSCCa (55% (17/31) versus 13% (2/15), P = 0.01). The most common combination of mutations occurred in only 23% (8/35) of evaluable MSI-positive cancers. Our findings suggest that the accumulation of specific genetic alterations in MSI-positive colorectal cancers is markedly heterogeneous, because the occurrence of some mutations (eg, ras, E2F-4, and Bax genes), but not others (eg, transforming growth factor beta type II receptor gene), depends on the underlying basis of the mismatch repair deficiency. This genetic heterogeneity may contribute to the heterogeneous clinical and pathological features of MSI-positive cancers. |
| Databáze: | OpenAIRE |
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