Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study
Background: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours. Methods: This prospective multicentric study involved 2...
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Published in | British journal of cancer Vol. 110; no. 11; pp. 2728 - 2737 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
27.05.2014
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Background:
To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours.
Methods:
This prospective multicentric study involved 251 stage I–III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12–13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4–9), CpG island methylation phenotype status, ploidy, S-phase, LOH.
Results:
The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in
KRAS
-mutated (
P
=0.005),
BRAF
wt (
P
=0.009) and pMMR tumours (
P
=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1
vs
1.4) and TP (median 5.8
vs
3.5) expression relative to pMMR (
P
<0.001) and show higher DPD expression (median 14.9
vs
7.9,
P
=0.027) and EGFR content (median 69
vs
38,
P
=0.037) relative to pMMR.
Conclusions:
Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0007-0920 1532-1827 |
DOI: | 10.1038/bjc.2014.213 |