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Molecular analysis of colorectal cancer tumors from patients with mismatch repair proficient hereditary nonpolyposis colorectal cancer suggests novel carcinogenic pathways.
Clin Cancer Res. 2007 Oct 01; 13(19):5729-35.CC

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+Show Affiliations

Laboratory of Molecular Oncology, Hospital Clínico San Carlos, Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17908962

Citation

Sánchez-de-Abajo, Ana, et al. "Molecular Analysis of Colorectal Cancer Tumors From Patients With Mismatch Repair Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 13, no. 19, 2007, pp. 5729-35.
Sánchez-de-Abajo A, de la Hoya M, van Puijenbroek M, et al. Molecular analysis of colorectal cancer tumors from patients with mismatch repair proficient hereditary nonpolyposis colorectal cancer suggests novel carcinogenic pathways. Clin Cancer Res. 2007;13(19):5729-35.
Sánchez-de-Abajo, A., de la Hoya, M., van Puijenbroek, M., Tosar, A., López-Asenjo, J. A., Díaz-Rubio, E., Morreau, H., & Caldes, T. (2007). Molecular analysis of colorectal cancer tumors from patients with mismatch repair proficient hereditary nonpolyposis colorectal cancer suggests novel carcinogenic pathways. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 13(19), 5729-35.
Sánchez-de-Abajo A, et al. Molecular Analysis of Colorectal Cancer Tumors From Patients With Mismatch Repair Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways. Clin Cancer Res. 2007 Oct 1;13(19):5729-35. PubMed PMID: 17908962.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular analysis of colorectal cancer tumors from patients with mismatch repair proficient hereditary nonpolyposis colorectal cancer suggests novel carcinogenic pathways. AU - Sánchez-de-Abajo,Ana, AU - de la Hoya,Miguel, AU - van Puijenbroek,Marjo, AU - Tosar,Alicia, AU - López-Asenjo,J A, AU - Díaz-Rubio,Eduardo, AU - Morreau,Hans, AU - Caldes,Trinidad, PY - 2007/10/3/pubmed PY - 2007/12/21/medline PY - 2007/10/3/entrez SP - 5729 EP - 35 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 13 IS - 19 N2 - 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. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/17908962/Molecular_analysis_of_colorectal_cancer_tumors_from_patients_with_mismatch_repair_proficient_hereditary_nonpolyposis_colorectal_cancer_suggests_novel_carcinogenic_pathways_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17908962 DB - PRIME DP - Unbound Medicine ER -