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Microsatellite instability, KRAS, BRAF and PIK3CA mutations in patients operated for stage II and III colorectal cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The aims of this study were to molecularly characterize tumors from disease stage II and III colorectal cancer (CRC) patients with regard to BRAF, PIK3CA, KRAS mutations and microsatellite instability (MSI) status, and to compare the frequency of the mutations in patients stratified by disease recurrences.

Material and methods

BRAF, PIK3CA, KRAS mutations and MSI status were analyzed in fresh frozen tumors from patients with CRC. The analyzed tissue was selected from curatively treated patients with disease stage II and III. These patients were stratified for disease recurrence; stage II without recurrence (n=19) and with recurrence (n=18) and stage III without recurrence (n=17) and stage III with recurrence (n=19).

 

 

Results

 

No major difference in frequency of mutations in BRAF, KRAS, PIK3CA and MSI was demonstrated between patients with or without recurrence or disease stages II-III. Occurrence of any of the analyzed mutations (BRAF, KRAS and PIKC3A) was more frequent when the tumor was localized in the colon (98%) versus the rectum (2%) (p=0.015). MSI tumors demonstrated a high frequency of BRAF mutations (63%) and a low frequency of KRAS mutations (1%). Tumors of patients without recurrence revealed higher frequency of MSI (p=0.038). BRAF mutations were more abundant in patients with stage III disease without recurrence (n=7) compared to stage III patients with recurrence (n=2). Patients with stage III disease and BRAF mutation had a better cancer specific survival, compared with patients in stage III without BRAF mutation (p=0.043).

 

Conclusion

 

The results indicate that patients with CRC stage III without recurrence have a higher frequency of BRAF mutation compared to stage III patients with recurrence, moreover those patients with stage III disease and BRAF mutation have better prognosis than those with stage III disease and no BRAF mutation.

National Category
Surgery
Identifiers
URN: urn:nbn:se:uu:diva-159140OAI: oai:DiVA.org:uu-159140DiVA: diva2:442587
Available from: 2011-09-22 Created: 2011-09-22 Last updated: 2011-11-04
In thesis
1. Cancer of the Colon and Rectum: Prognostic Factors and Early Detection
Open this publication in new window or tab >>Cancer of the Colon and Rectum: Prognostic Factors and Early Detection
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Colorectal cancer (CRC) is one of the most common causes of death from malignant disease. Nevertheless, no ideal screening method exists and there is a lack of prognostic and predictive factors to support clinical decisions and to aid the development of a more individualized treatment for patients with CRC. The aim of this thesis was to investigate early detection, prognostic and predictive factors of CRC. In the first paper, a novel method to collect cells for DNA quantification from the rectal mucosa was investigated. The sensitivity and specificity of this test to detect CRC or any pathology in colon and rectum were ultimately too low to be acceptable. In the second paper, the prognostic value of growth differentiation factor 15 (GDF 15) was evaluated in patients curatively operated for colorectal cancer. GDF 15 expression was demonstrated to be associated with a negative prognosis in patients with stages I-III and III disease. In the third paper, the prognostic value of BRAF, PIK3CA KRAS and MSI was evaluated in a cohort of patients with CRC stratified by disease and recurrence. The results indicated that patients with CRC stage III without recurrence have a higher frequency of BRAF mutation compared to stage III patients with recurrence. In the fourth paper, histopathological predictors of pathologic complete response (pCR) as well as the association between pre-treatment carcinoembryonic antigen (CEA) levels and pCR in non-smoking and smoking patients receiving preoperative chemo-radiotherapy for rectal cancer were evaluated. Only in non-smokers was a low CEA level significantly associated with pCR, suggesting that the predictive value of CEA for pCR in rectal cancer in smokers can be limited. In sum, this research has investigated a new method for CRC detection and further evaluated the clinical use of prognostic and predictive markers in CRC.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 83 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 706
Keyword
colorectal cancer screening predictive markers prognostic markers
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-159142 (URN)978-91-554-8166-7 (ISBN)
Public defence
2011-11-04, Hedstrand salen, Akademiska sjuhuset, ing. 70 bv, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-10-14 Created: 2011-09-22 Last updated: 2012-06-14Bibliographically approved

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Wallin, Ulrik

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