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Colorectal Cancer: Aspects of Heredity, Prognosis and Tumour Markers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
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 [en]
colorectal cancer, heredity, Tryptophanyl t-RNA synthetase, microsatellite instability, SP-PLA, prognosis, biomarkers
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-224624ISBN: 978-91-554-8975-5 (print)OAI: oai:DiVA.org:uu-224624DiVA: diva2:717427
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
List of papers
1. The correlation between a family history of colorectal cancer and survival of patients with colorectal cancer
Open this publication in new window or tab >>The correlation between a family history of colorectal cancer and survival of patients with colorectal cancer
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2009 (English)In: Familial Cancer, ISSN 1389-9600, E-ISSN 1573-7292, Vol. 8, no 4, 555-561 p.Article in journal (Refereed) Published
Abstract [en]

The purpose was to analyze survival of patients with colorectal cancer and a positive family history for colorectal cancer in first degree relatives compared with those with no such family history and to determine whether differences in survival could be explained by known clinico-pathological factors. During 2000-2003, 318 consecutive patients with colorectal cancer answered a written questionnaire about their family history for colorectal cancer. During a 6-year follow-up, recurrences and survival were registered. Thirty-one (10%) patients had a first-degree relative with colorectal cancer, moreover two patients fulfilled the criteria of hereditary non-polyposis colorectal cancer and were excluded. Patients with a first-degree relative with colorectal cancer had better survival and lower risk for recurrences compared to those with no relatives with colorectal cancer. In a multivariate analysis including age, gender, stage of disease, tumor differentiation, vascular invasion and family history, patients with first-degree relatives with colorectal cancer had lower risks for death (RR 0.37; 95% CI 0.17-0.78) and death from cancer (RR 0.25; 95% CI 0.08-0.80), compared to those with a no relative with colorectal cancer. The differences were seen in patients with colon cancer but not rectal cancer. Family history for colorectal cancer in a first-degree relative is an individual prognostic factor in patients with colon cancer and could not be explained by known clinico-pathological factors. The value of family history taking in patients with colon cancer is therefore not only to identify families with hereditary colorectal cancer, but also to add information to the prognosis of the patients.

Keyword
Cancer, Family history, Heredity, Colorectal, Survival
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-110794 (URN)10.1007/s10689-009-9286-0 (DOI)000271399200038 ()19714489 (PubMedID)
Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2014-07-25Bibliographically approved
2. The prognostic significance of tryptophanyl-tRNA synthetase in colorectal cancer
Open this publication in new window or tab >>The prognostic significance of tryptophanyl-tRNA synthetase in colorectal cancer
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2009 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 11, 2949-2956 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Tryptophanyl-tRNA synthetase (TrpRS) is an aminoacyl-tRNA synthetase involved in protein synthesis and regulation of RNA transcription and translation and is an inhibitor of angiogenesis. TrpRS has been shown to be differentially expressed in colorectal cancer (CRC) and has thus been identified as a potential prognostic marker. The aim of this study was to analyze the correlation of TrpRS to the prognosis of patients diagnosed and treated for CRC within a defined population. METHODS: With a polyclonal, monospecific IgG antibody, TrpRS expression was assessed by immunohistochemistry on tissue microarrays with tumors from a population-based CRC cohort (n = 320). Staining intensity and fraction of positive tumor cells were recorded. A Cox multivariate model including TrpRS expression, carcinoembryonic antigen, age, stage, tumor differentiation, and lymphatic and vascular vessel invasion was used to calculate the hazard ratio and 95% confidence interval (95% CI) for time to recurrence, disease-free survival, and overall survival. RESULTS: Low expression of TrpRS correlated to increased risk for lymph node metastasis (P = 0.025) and a more advanced tumor stage (P = 0.001). Patients with tumors and increased levels of TrpRS expression had better survival than patients with low expression levels. Multivariate analyses revealed significantly better disease-free survival (relative risk, 0.59; 95% CI, 0.38-0.95) for patients with high expression than for patients with low expression of TrpRS. For colon cancer patients, a reduced risk for recurrence was seen in patients with increased TrpRS expression (relative risk, 0.23; 95% CI, 0.07-0.80). CONCLUSION: Low expression of TrpRS in tumor tissue correlates with increased risk for recurrence and worse survival in patients with CRC. This can be related to its antiangiogenic properties and could aid in the future selection of new drugs in the treatment of CRC.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-113326 (URN)10.1158/1055-9965.EPI-09-0456 (DOI)000271562600022 ()19900940 (PubMedID)
Available from: 2010-01-27 Created: 2010-01-27 Last updated: 2014-07-25Bibliographically approved
3. Associations of defect mismatch repair genes with prognosis and heredity in sporadic colorectal cancer
Open this publication in new window or tab >>Associations of defect mismatch repair genes with prognosis and heredity in sporadic colorectal cancer
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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.

 

Keyword
colorectal cancer, MSI, heredity, prognosis
National Category
Cancer and Oncology Surgery
Identifiers
urn:nbn:se:uu:diva-224695 (URN)10.1016/j.ejso.2016.10.013 (DOI)000394072300011 ()27836416 (PubMedID)
Available from: 2014-05-19 Created: 2014-05-19 Last updated: 2017-04-25Bibliographically approved
4. Detection of prognostic biomarkers with solid-phase proximity ligation assay in patients with colorectal cancer
Open this publication in new window or tab >>Detection of prognostic biomarkers with solid-phase proximity ligation assay in patients with colorectal cancer
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2016 (English)In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 9, no 3, 251-255 p.Article in journal (Refereed) Published
Abstract [en]

Background: In the search for prognostic biomarkers a significant amount of precious biobanked blood samples is needed if conventional analyses are used. Solid-phase proximity ligation assay (SP-PLA) is an analytic method with the ability to analyse many proteins at the same time in small amounts of plasma. The aim of this study was to explore the potential use of  SP-PLA in patients with colorectal cancer (CRC).

Material and methods: Plasma from patients with stage I-IV CRC, with (n=31) and without (n=29) disease dissemination at diagnosis or later, was analysed with SP-PLA using 35 antibodies targeting an equal number of proteins in 5 ml plasma. Carcinoembryonic antigen (CEA), analysed earlier on this cohort, was used as a reference.

Results: A total of 21 of the 35 proteins were detectable with SP-PLA. Patients in stage II-III with disseminated disease had lower plasma concentrations of HCC-4 (p=0.025). Low plasma levels of TIMP-1 were seen in patients with disseminated disease stage II (p=0.003). The level of CEA was higher in patients with disease dissemination compared to those without (p=0.007).

Conclusion: SP-PLA has the ability to analyse many tumour markers simultaneously in a small amount of blood. However, none of the markers selected for the present SP-PLA analyses gave better prognostic information compared with CEA. 

Keyword
colorectal cancer, biomarkers, SP-PLA, recurrence, prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-224696 (URN)10.1016/j.tranon.2016.04.001 (DOI)000378028300014 ()27267845 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 294409; 259796
Available from: 2014-05-19 Created: 2014-05-19 Last updated: 2017-12-05Bibliographically approved

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