The clinical and molecular epidemiology of inherited colorectal cancer in Newfoundland and Labrador

Wish, Tyler (2012) The clinical and molecular epidemiology of inherited colorectal cancer in Newfoundland and Labrador. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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    Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
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Abstract

Background -- Colorectal cancer (CRC) is a hereditary disease and approximately one-third of all patients have a family history of CRC. A greater understanding of the clinical and molecular features associated with hereditary CRC may lead to improved screening and patient outcomes. The purpose of this thesis is to investigate the clinical, molecular and environmental features that are associated with CRC patients who have a family history of the disease. -- Methods -- Incident population-based CRC patients from Newfoundland and Labrador were prospectively identified from the Newfoundland Colorectal Cancer Registry (NFCCR). Eligible index patients (n = 1,173) were diagnosd at less than 75 years of age and eligible study controls (n = 1,603) were identified through random digit dialing. Consenting patients (n = 750) provided a blood sample and permission to access medical records and tissue blocks. Biological specimens underwent molecular testing for germline mutations in the mismatch repair genes (i.e. Lynch Syndrome), tumour microsatellite-instability and for the somatic p. V600E BRAF mutation. Patients and controls completed family history, personal history and food frequency questionnaires. -- Results -- Thirty-two percent of index patients (n = 179 / 553) had at least one firstdegree relative (FDR) affected by CRC. High-risk patients contained either a pathogenic mismatch repair gene variant (n = 17), or satisfied high-risk family history criteria, defined by either the familial CRC type X (FCCTX) (n = 15) or modified-FCCTX criteria (n = 16). The risk of CRC in family members of patients identified as FCCTX and modified-FCCTX is similar, but is significantly less when compared to Lynch syndrome. Twenty-six percent of non high-risk patients had at least one FDR affected by CRC. Patients who had either a synchronous or metachronous tumour or a V600E BRAF mutation tumour were associated with a significantly greater family history of CRC compared to patients without either of these features. Patients who have a V600E BRAF mutation tumour are significantly associated with diabetes, smoking and inversely associated with non-steroidal anti-inflammatory drugs. -- Conclusions -- The incidence of hereditary colorectal cancer in NL is high. A small subgroup of patients satisfies high-risk criteria, but the etiology of the disease is unknown for the majority of these families and requires further investigation. The V600E BRAF mutation and the occurrence of multiple tumours are associated with an elevated family history of CRC and may be useful markers of increased risk for screening purposes. Metabolic and inflammatory mechanisms may be important factors in the etiology of patients who have a BRAF mutation tumour.

Item Type: Thesis (Doctoral (PhD))
URI: http://research.library.mun.ca/id/eprint/2415
Item ID: 2415
Additional Information: Includes bibliographical references (leaves 112-131).
Department(s): Medicine, Faculty of
Date: 2012
Date Type: Submission
Geographic Location: Canada--Newfoundland and Labrador
Library of Congress Subject Heading: Colon (Anatomy)--Cancer--Newfoundland and Labrador--Etiology; Colon (Anatomy)--Cancer--Newfoundland and Labrador--Epidemiology; Colon (Anatomy)--Cancer--Newfoundland and Labrador--Genetic aspects; Colon (Anatomy)--Cancer--Newfoundland and Labrador--Molecular aspects; Colon (Anatomy)--Cancer--Environmental aspects--Newfoundland and Labrador
Medical Subject Heading: Colonic Neoplasms--etiology--Newfoundland and Labrador; Colonic Neoplasms--epidemiology--Newfoundland and Labrador; Colonic Neoplasms--genetics--Newfoundland and Labrador; Environment

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