Molecular analysis of colorectal cancer tumors from patients with mismatch repair proficient hereditary nonpolyposis colorectal cancer suggests novel carcinogenic pathways.

Abstract

PURPOSE:

A subset of colorectal cancers (CRC) arises in families that, despite fulfilling clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC), do not show evidence of a mismatch repair (MMR) deficiency. The main objective of this study was to characterize these tumors at the molecular level.

EXPERIMENTAL DESIGN:

After comprehensive germ line mutation scanning, microsatellite analysis, and MMR protein expressions, we selected a well-defined cohort of 57 colorectal tumors with no evidence of MMR defects. In this group of tumors, we analyzed KRAS, BRAF, and APC somatic mutations, as well as methylguanine methyltransferase (MGMT) and beta-catenin expression. We correlated these alterations with clinicopathologic data and explored the relationship between KRAS G > A transitions and lack of MGMT expression.

RESULTS:

The mutation profile at the RAS/RAF/MAPK pathway mimics sporadic microsatellite-stable CRCs. We found an average age of diagnosis 10 years older in KRAS-mutated patients (P = 0.001). In addition, we show that KRAS G > A transitions are actively selected by tumors, regardless of MGMT status. Similarities with HNPCC high-microsatellite instability tumors are observed when APC data are analyzed. The APC mutation rate was low and small insertions/deletions accounted for 70% of the alterations. In addition, we found a low frequency of beta-catenin nuclear staining. Finally, we did not find evidence of tumors arising in individuals from the same family sharing molecular features.

CONCLUSIONS:

We show evidence that CRC tumors arising in HNPCC families without MMR alterations have distinctive molecular features. Overall, our work shows that systematic analysis of somatic alterations in a well-defined subset of CRCs is a good approach to provide new insights into the mechanisms of colorectal carcinogenesis.

• Authors: Ana Sánchez-de-Abajo, Miguel de la Hoya, Marjo van Puijenbroek, Alicia Tosar, J A López-Asenjo, Eduardo Díaz-Rubio, Hans Morreau, Trinidad Caldes
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 19 Pg. 5729-35 (Oct 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17908962 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• beta Catenin

Topics

• Aged
• Cohort Studies
• Colorectal Neoplasms (genetics, metabolism)
• Colorectal Neoplasms, Hereditary Nonpolyposis (genetics)
• DNA Mismatch Repair
• Female
• Gene Expression Profiling
• Germ-Line Mutation
• Humans
• Male
• Microsatellite Repeats
• Middle Aged
• Models, Biological
• Neoplasms (metabolism)
• beta Catenin (metabolism)