Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences

Takato Fujiwara, Joshua M. Stolker, Toshiaki Watanabe, Asif Rashid, Patti Longo, James R. Eshleman, Susan Booker, Henry T. Lynch, Jeremy R. Jass, Jane S. Green, Hoguen Kim, Jin Jen, Bert Vogelstein, Stanley R. Hamilton

Research output: Contribution to journalArticle

Abstract

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 (P < 0.000001), 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 Kras 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 β 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 hMLH1 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 β 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.

Original languageEnglish (US)
Pages (from-to)1063-1078
Number of pages16
JournalAmerican Journal of Pathology
Volume153
Issue number4
DOIs
StatePublished - Oct 1998

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Fujiwara, T., Stolker, J. M., Watanabe, T., Rashid, A., Longo, P., Eshleman, J. R., Booker, S., Lynch, H. T., Jass, J. R., Green, J. S., Kim, H., Jen, J., Vogelstein, B., & Hamilton, S. R. (1998). Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences. American Journal of Pathology, 153(4), 1063-1078. https://doi.org/10.1016/S0002-9440(10)65651-9