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Associations of defect mismatch repair genes with prognosis and heredity in sporadic colorectal cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
Lund Univ, Div Oncol Pathol, Dept Clin Sci, Lund, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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2017 (English)In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 43, no 2, 311-321 p.Article in journal (Refereed) Published
Abstract [en]

Background: Microsatellite instability arises due to defect mismatch repair (MMR) and occurs in 10-20% of sporadic colorectal cancer. The purpose was to investigate correlations between defect MMR, prognosis and heredity for colorectal cancer in first-degree relatives.

Material and methods: Tumour tissues from 320 patients consecutively operated for colorectal cancer were analysed for immunohistochemical expression of MLH1, MSH2 and MSH6 on tissue microarrays. Information on KRAS and BRAF mutation status was available for selected cases.

Results: Forty-seven (15%) tumours displayed MSI. No correlation was seen between patients exhibiting MSI in the tumour and heredity (p= 1.000). Patients with proximal colon cancer and MSI had an improved cancer-specific survival (p= 0.006) and prolonged time to recurrence (p= 0.040). In a multivariate analysis including MSI status, gender, CEA, vascular and neural invasion, patients with MSS and proximal colon cancer had an impaired cancer-specific survival compared with patients with MSI (HR, 3.87; CI, 1.36-11.01). The same prognostic information was potentially also in distal colon cancer; no recurrences seen in the 8 patients with stages II and III distal colon cancer and MSI, but the difference was not statistically significant.  Conclusion:No correlation between MSI and heredity was seen. Patients with MSI tumours had improved survival.

 

Place, publisher, year, edition, pages
2017. Vol. 43, no 2, 311-321 p.
Keyword [en]
colorectal cancer, MSI, heredity, prognosis
National Category
Cancer and Oncology Surgery
Identifiers
URN: urn:nbn:se:uu:diva-224695DOI: 10.1016/j.ejso.2016.10.013ISI: 000394072300011PubMedID: 27836416OAI: oai:DiVA.org:uu-224695DiVA: diva2:717855
Available from: 2014-05-19 Created: 2014-05-19 Last updated: 2017-04-25Bibliographically approved
In thesis
1. Colorectal Cancer: Aspects of Heredity, Prognosis and Tumour Markers
Open this publication in new window or tab >>Colorectal Cancer: Aspects of Heredity, Prognosis and Tumour Markers
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Colorectal cancer (CRC) is one of the most common cancer types and leading causes of cancer death worldwide. Since CRC is a heterogenic disease, there is a demand for increased knowledge of the underlying genetic and epigenetic mechanisms. The aim of this thesis was to investigate heredity and potential tumour markers in relation to prognosis. In paper I, survival of patients with CRC and a positive family history of CRC in first-degree relatives was analysed. Patients with colon cancer and positive family history of CRC had improved survival compared to patients with negative family history. This improvement in survival could not be explained by known clinico-pathological factors. In paper II, we investigated the prognostic value of Tryptophanyl t-RNA synthetase (TrpRS) in tissues from patients operated for CRC. Low protein expression of TrpRS in primary tumour tissues correlated with increased risk of recurrence and poorer survival. In paper III, the prognostic value of microsatellite instability (MSI) and the correlation to heredity for CRC in first-degree relatives was investigated. Patients with proximal colon cancer and MSI had improved cancer specific survival. There were no correlation between MSI and heredity. In paper IV, we evaluated the potential use of proximity ligation assay (SP-PLA) in patients with CRC, by simultaneous analysis of 35 proteins in only 5 μl plasma. SP-PLA is a suitable method for protein detection and might give valuable guidance in pursuing new prognostic and predictive tumour markers. However, none of the markers selected for present SP-PLA analyses gave better prognostic information than CEA. In conclusion, heredity is related to better survival independent of MSI in patients with CRC and MSI is associated with better prognosis in proximal colon cancer. Detection and increased knowledge of molecular mechanism in CRC is important, however it needs to be further investigated and validated in clinical use. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1011
Keyword
colorectal cancer, heredity, Tryptophanyl t-RNA synthetase, microsatellite instability, SP-PLA, prognosis, biomarkers
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-224624 (URN)978-91-554-8975-5 (ISBN)
Public defence
2014-09-06, Grönwallsalen, Akademiska sjukhuset, ingång 70, bv, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2014-06-13 Created: 2014-05-15 Last updated: 2014-07-25

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Ghanipour, LanaSundström, MagnusGlimelius, BengtPåhlman, LarsBirgisson, Helgi

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Colorectal SurgeryDepartment of Immunology, Genetics and PathologyDepartment of Radiology, Oncology and Radiation Science
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European Journal of Surgical Oncology
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