Project: Research project

Project Details


This is an R21 application to determine the prognostic value of assays of
genomic instability in human colon cancer. It focuses on the fact that
instability, though determined by the presence of mutations in DNA mismatch
repair genes, is a complex phenotype exhibiting differences in instability
at different loci (eg oligo A versus microsatellite) and variability in
quantitative extent of instability at a given locus. Thus, such variable
penetrance of the mutations would have an impact on clinical utility of
these markers. Further, clear demonstration of variable penetrance would
raise the possibility that environment (eg diet), the other major risk
factor for colonic cancer, can affect the instability phenotype.

DNA already isolated from over 1300 tissue samples representing more than
700 patients on 2 phase III studies for adjuvant therapy for Duke' B and C
tumors carried out by the Eastern Cooperative Oncology Group (ECOG) will be
utilized to: 1) determine the prognostic value of genomic instability on
recurrence and survival; 2) determine the relative prognostic value of
instability at oligo A versus microsatellite sequences; 3) determine the
prognostic value of a novel measurement of quantitative extent of genomic
instability; 40 determine whether low levels of instability can be detected
in normal mucosa of patients with Dukes' B and C tumors. Of particular
note, one of the phase III studies which has supplied material contains a
surgery only arm. Since adjuvant therapy is now recommended for all
resectable Dukes'B and C patients, this represents the last opportunity to
study the relationship of genetic alterations to the natural history of the

The loci to be investigated for instability include; oligo A sequences in
two cDNA sequences which we have identified as overexpressed in flat
colonic mucosa at risk for colon tumor development; a CA microsatellite and
an oligo A sequence in the 3; transcribed, but untranslated region, of the
cyclin D1 gene; an oligo A in the 4th exon of the PCNA gene; a CA
microsatellite in the RB gene; and a CA microsatellite upstream of the apoD
gene. Statistical analysis will be carried out through an ongoing
collaboration with ECOG Biostatistics at the Dana-Farber, which maintains
a complete clinical data base on these patients. Moreover, novel
statistical methods will explore the relationship between genetic
instability and risk of relapse.
Effective start/end date5/1/954/30/97


  • Genetics


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