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

Colorectal cancer is a serious health problem in Western societies. In Sweden it is the second most common malignancy among females, and the third in males, and the third leading cause of cancer related death in both sexes. To date it is known that several biological pathways can lead to colorectal cancer. An enhanced understanding of the molecular and cellular events occurring within these pathways should ultimately result in better tailored preventive, diagnostic and therapeutic approaches. An important goal is to identify cancer predisposing genetic variants that would make genetic screening of at-risk individuals possible, and to find parametres which could define homogenous subgroups associated with a certain prognosis.

Impaired apoptotic processes have been implicated in colorectal tumourigenesis. In order to explore the significance of apoptosis in relation to proliferative activity, and other clinicopatological data including prognosis, apoptotic rates were measured by TUNEL in 158 colorectal tumours. A significant increase of apoptotic rate was observed with advancing tumour stage, from Dukes' A to D. Apoptotic rates were further significantly associated with the proliferative activity in the tumour, indicated by the proliferating cell nuclear antigen (PCNA). Thus it seems that apoptotic levels in the tumour might reflect tumour progression, and further that the processes of apoptosis and proliferation are coupled. Apoptosis was not related to p53, bcl-2 or K-ras, and did not confer any additional prognostic information.

APC has been referred to as a "gatekeeper" in the progression of colorectal cancer. It is in a key position to regulate the balance between cell adhesion and migration and may also be involved in proliferation and apoptosis. The two germ line APC variants I1307K and E1317Q have been associated with increased colorectal cancer risk in certain populations, but have yet never been investigated in Swedish colorectal cancer patients. We screened J 94 colorectal cancer patients with and without a family history of colorectal cancer by DNA sequencing analysis, but did not find any of the variants. We conclude that I1307K and E1317Q are rare or absent in this population and should not confer any increased colorectal cancer risk in the Swedish population.

The microsatellite instability pathway accounts for the majority of tumours in hereditary non-polyposis colorectal cancer (HNPCC) patients and about 15% of sporadic colorectal cancer cases. Inactivated mismatch repair (MMR) genes leads to an increased mutation rate, especially within repetitive DNA sequencies called microsatellites which are prone to replication errors, a phenomenon referred to as microsatellite instability (MSI). Several genes with microsatellites within their coding regions are targeted by MSI, and are possibly involved in tumourigenesis, including the repair gene MBD4 which is involved in maintaining the integrity of genomic methylation patterns. We aimed to determine the microsatellite status of 201 colorectal tumours using the marker Bat 26 in order to evaluate the relationship of MSI and clinicopathological variables including survival. We further aimed to investigate whether MBD4 is a MSI target gene in colorectal cancer, and to search for mutational associations with clinicopathological factors to reveal eventual phenotypical effects. Surprisingly, MSI was not associated with survival, as opposed to many previous studies, suggesting that the prognostic significance and the factors associated with it demands further investigation. MBD4 seemed to be a target of MSI, since the mutations were restricted only to MSI tumours. The clinicopathological variables associated with the MBD4 mutated tumours were likely the reflection of MSI features aquired prior to the MBD4 mutation, including right colon location and mucinous histology. The significance of these mutations remains to be determined in a largermaterial.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2002. , 61 p.
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 52
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25728Local ID: 10106ISBN: 91-7373-157-9 (print)OAI: oai:DiVA.org:liu-25728DiVA: diva2:246276
Presentation
2002-01-31, Lab 1, Sal 1, Universitetssjukhuset, Linköping, 13:00 (Swedish)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2013-07-11
List of papers
1. Apoptosis in relation to proliferating cell nuclear antigen and Dukes' stage in colorectal adenocarcinoma
Open this publication in new window or tab >>Apoptosis in relation to proliferating cell nuclear antigen and Dukes' stage in colorectal adenocarcinoma
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1999 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 15, no 1, 53-58 p.Article in journal (Refereed) Published
Abstract [en]

Colorectal cancer is a disease that is associated with default in the balance of apoptotic regulation. In the present study apoptosis was examined in 158 colorectal adenocarcinomas using the terminal deoxynucleotidyl transferase mediated digoxigenin nick end labeling (TUNEL) method. The median apoptotic index (AI) was 0.95% (range 0-6. 68%). Eighty-two tumours exhibited AI 0.95%. We revealed a positive correlation between apoptosis and proliferation determined as the expression of proliferating cell nuclear antigen (PCNA, p=0.002). The frequency of apoptosis increased from Dukes' stage A, B, C to D (p=0.01). No correlations were found between apoptosis and the patients' sex, age, tumour location, growth pattern, differentiation, prognosis, bcl-2, p53 or K-ras. Our findings suggest that we should further investigate the relationship between apoptosis and cellular proliferative activity in colorectal cancer to evaluate whether this might provide additional information in the selection of patients for effective adjuvant therapy.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25007 (URN)000081089400006 ()10375593 (PubMedID)9428 (Local ID)9428 (Archive number)9428 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
2. APC I1307K and E1317Q variants are rare or do not occur in Swedish colorectal cancer patients
Open this publication in new window or tab >>APC I1307K and E1317Q variants are rare or do not occur in Swedish colorectal cancer patients
2001 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 37, no 4, 499-502 p.Article in journal (Refereed) Published
Abstract [en]

Recently, a germ line mutation of the APC gene, I1307K, was discovered in a subset of Ashkenazi jews. The mutation involves an amino acid exchange and creates a tract consisting of eight contiguous adenosine residues believed to cause hypermutability in this region. Another germ line missense variant, E1317Q, not restricted to a certain ethnic population, could functionally alter the protein. These APC variants have been linked with increased colorectal cancer risk in several studies. However, they have not yet been investigated in Swedish colorectal cancer patients. Thus, our aim was to investigate the prevalence of I1307K and E1317Q in Swedish colorectal cancer patients in order to determine if these genetic variants are important predisposing factors to colorectal cancer in this population. To this end, sequence analysis was carried out of the APC gene in order to identify any I1307K and E1317Q variants in 106 unselected cases and 88 hereditary/familial colorectal cancer cases including 22 cases of hereditary non-polyposis colorectal cancer (HNPCC) fulfilling the Amsterdam criteria. Out of a total of 194 cases examined, we did not find any variants. It seems that these alterations are rare or absent in the Swedish population.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25006 (URN)10.1016/S0959-8049(00)00393-2 (DOI)000167739600020 ()11267860 (PubMedID)9427 (Local ID)9427 (Archive number)9427 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13
3. Microsatellite instability and MBD4 mutation in unselected colorectal cancer
Open this publication in new window or tab >>Microsatellite instability and MBD4 mutation in unselected colorectal cancer
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2003 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 23, no 4, 3569-3574 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: We investigated the prognostic significance of microsatellite instability (MSI) and the association with clinicopathological factors in colorectal cancer, and further identified MBD4 mutations and their clinicopathological significance.

PATIENTS AND METHODS: MSI was analyzed in 201 colorectal cancers. Sequencing analysis of MBD4 was performed in 26 MSI and 28 microsatellite stable (MSS) tumors.

RESULTS: Twenty-seven tumors (13.4%) were MSI but did not correlate with improved survival. MSI was significantly correlated with proximal colon tumors (p < 0.001), poor differentiation or mucinous type (p = 0.005) and multiple tumors (p = 0.04). MBD4 mutations were found in 15% MSI but not in MSS tumors. The mutated cases showed female overrepresentation, proximal site and poorly-differentiated/mucinous type.

CONCLUSION: MSI was not correlated with survival, but shared other features associated with MSI in colorectal cancer as demonstrated by others. The clinicopathological variables associated with the MBD4 mutations were probably the reflection of MSI features.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25002 (URN)000184723600067 ()12926109 (PubMedID)9422 (Local ID)9422 (Archive number)9422 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13

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