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Molecular alterations in colorectal cancer
Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Colorectal cancer is one of the most common causes to death due to cancer in the world. It is important to understand the molecular mechanisms behind tumour development for both prognostic and therapeutic applications. In this thesis, we have focused on genes and proteins related to tumour suppressor function, apoptosis and DNA repair in patients with colorectal adenocarcinomas. In Paper I, the pattern of mutations affecting the tumour suppressor p53 was investigated in 75 cases in order to determine whether there were any specific mutations in the cases with p53 accumulated in the cytoplasm. We found that the frequency and pattern of mutation were similar to those with nuclear p53 expression, suggesting that the prognostic importance of cytoplasmic p53 accumulation may depend on both mutational and non-mutational mechanisms. In Paper II we investigated the protein expression of the pro-apoptotic gene Bax from normal mucosa to primary tumour and to regional lymph node metastases in 135 patients. We further examined Bax mutations and the microsatellite status in the primary tumours. Bax expression was stronger from normal to tumour tissue, but decreased in the metastases. The matched cases with lower expression in the metastastases than in the primary tumour showed a more infiltrative growth pattern and more distal metastases. In paper III the mRNA expression of the pro-apoptotic gene Noxa was examined with real-time PCR and mutations searched for in 94 colorectal tumours and the corresponding normal mucosa. Noxa mRNA expression was weak in 9% and strong in 2% of the tumours and decreased in 9% and increased in 16% of the tumours compared to the normal mucosa. The expression was not related to clinicopathological features. We did not find any mutations in the gene. In Paper IV we studied the biological and clinicopathological importance of protein expression of the mismatch repair genes hMLHJ, hMSH2, hMSH3 and hMSH6 individually or combined in 301 colorectal cancers. When analysed individually, hMLH1 and hMSH2 were more important and the combined groups were more related to the mutator pathway, suggesting that the combined deficiencies of the proteins are more efficiently involved in the mutator pathway. Our result from comparing weak versus strong staining may suggest that the intensity of staining should be considered in future studies on the expression of mismatch repair proteins.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2002. , 92 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 743
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25665Local ID: 10041ISBN: 91-7373-183-8 (print)OAI: oai:DiVA.org:liu-25665DiVA: diva2:246213
Public defence
2002-10-04, Administrationsbyggnadens aula, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-20Bibliographically approved
List of papers
1. p53 mutations are present in colorectal cancer with cytoplasmic p53 accumulation
Open this publication in new window or tab >>p53 mutations are present in colorectal cancer with cytoplasmic p53 accumulation
2001 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 92, no 3, 338-341 p.Article in journal (Refereed) Published
Abstract [en]

Previous studies have shown that nuclear p53 over-expression is an indicator of p53 mutations whereas cytoplasmic p53 accumulation is related to wild-type p53 in several kinds of tumors. Cytoplasmic p53 accumulation has been demonstrated to be an independent prognostic factor in colorectal adenocarcinomas. The purpose was to examine whether mutations occur in cases with p53 accumulated in the cytoplasm and whether there are any differences in the frequency and characteristics of p53 mutations in different staining patterns. In the present study, we identified p53 mutations using PCR single-strand conformation polymorphism (SSCP) and DNA sequencing in 75 primary colorectal adenocarcinomas with different staining patterns (negative, nucleus, cytoplasm, nucleus and cytoplasm). The results show that the frequency and nature of mutations in tumors with cytoplasmic p53 accumulation were similar to those with nuclear p53 expression. However, the tumors with accumulation in both the nucleus and cytoplasm demonstrated a higher mutation rate. We suppose that the role of cytoplasmic p53 accumulation in predicting prognosis in patients with colorectal cancer may be dependent on both mutational and non-mutational mechanisms.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25033 (URN)10.1002/ijc.1189 (DOI)9456 (Local ID)9456 (Archive number)9456 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
2. Bax expression decreases significantly from primary tumor to metastasis in colorectal cancer
Open this publication in new window or tab >>Bax expression decreases significantly from primary tumor to metastasis in colorectal cancer
2002 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 20, no 3, 811-816 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Bax is a proapoptotic member of the bcl-2 family. Previous studies about Bax have shown that the expression increases from normal to tumor tissue, but the clinical significance is contradictory. Our aims were to analyze the expression of Bax from normal mucosa to primary tumor and to metastases in colorectal cancer patient. We further investigated whether low Bax expression in the primary tumor or changed expression from normal mucosa to primary tumor and to metastases had biologic and clinical significance.

PATIENTS AND METHODS: The study included 135 patients with primary colorectal adenocarcinoma, of whom 31 had metastases in the lymph nodes and 75 had normal mucosa. Immunohistochemistry, DNA sequencing, and microsatellite analysis were used to detect Bax expression, mutations, and microsatellite instability.

RESULTS: The protein was observed in 132 of 135 tumors, all normal epithelial cells and metastases. The frequencies of weak expression were greater from well/moderately to poorly differentiated and to mucinous carcinomas. Bax expression was stronger from normal to tumor tissue, but subsequently decreased in metastases. The matched cases with lower expression in the metastases than in the primary tumor showed a more infiltrative growth pattern and more distal metastases.

CONCLUSION: The association of Bax expression with tumor differentiation/histologic types and a decreased expression in the metastases, suggests that Bax expression may be involved in tumor differentiation/histologic types and metastatic progression. We also propose the novel notion that changed Bax expression in the metastases compared with the primary tumors might provide information to determine the clinicopathologic characteristics of the tumor.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25112 (URN)10.1200/JCO.20.3.811 (DOI)9545 (Local ID)9545 (Archive number)9545 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
3. The BH3-only member Noxa may not be involved in the development of unselected colorectal cancer
Open this publication in new window or tab >>The BH3-only member Noxa may not be involved in the development of unselected colorectal cancer
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Noxa is an BH3-only member of the Bcl-2 family, upregulated by p53 as a response to DNA damage. Mutations in the BH3-only region of other BH3-only members lead to an inactive protein. We have investigated the mRNA expression of Noxa with real-time PCR in 94 unselected colorectal adenocarcinomas and the corresponding normal mucosa. Further, we searched for mutations in the Noxa gene using single stranded conformation polymorphism and DNA sequencing. The mRNA expression of Noxa was weak in 9% and strong in 2% of the tumours and decreased in 9% and increased in 16% of the tumours compared to the normal mucosa, but these changes did not have any clinical or pathological significance. We did not find any mutations in the gene. Thus, our observations suggest that the variations in Noxa gene may not be of particular importance in the development of unselected colorectal cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81663 (URN)
Available from: 2012-09-20 Created: 2012-09-20 Last updated: 2012-09-20Bibliographically approved
4. Combined deficiency of hMLH1, hMSH2, hMSH3 and hMSH6 is an independent prognostic factor in colorectal cancer
Open this publication in new window or tab >>Combined deficiency of hMLH1, hMSH2, hMSH3 and hMSH6 is an independent prognostic factor in colorectal cancer
2003 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 22, no 1, 41-49 p.Article in journal (Refereed) Published
Abstract [en]

We examined biological and clinicopathological significance of individual and combined hMLH1, hMSH2, hMSH3 and hMSH6 expression with immunohistochemistry in 301 unselected colorectal cancers. Weak hMLH1 expression was correlated to microsatellite instability (P=0.04), negative p53 expression (P=0.005) and mucinous carcinomas (P=0.02). Weak hMSH2 expression was related to negative ras (P<0.001) and p53 expression (P=0.005), and better survival (P=0.03). hMSH2, hMSH3 and hMSH6, as well as hMLH1, hMSH2, hMSH3 and hMSH6, were combined into a 'functional' and a 'less-functional' group, respectively. Both 'less-functional' groups were/tended to be associated with microsatellite instability, negative ras and p53 expression, and better survival. In summary, hMLH1 and hMSH2 were more important when investigated individually, and the combined groups were more related to the mutator pathway, suggesting that combined deficiencies of the proteins are more efficiently involved in the mutator pathway. Our result from weak versus strong staining may suggest that the intensity of staining should be considered in future studies on mismatch repair proteins.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25113 (URN)12469183 (PubMedID)9546 (Local ID)9546 (Archive number)9546 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved

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