Genetic contribution to colorectal cancer in Newfoundland and Labrador based on family history and tumour molecular analyses for an incident cohort

Crane, Amanda (2012) Genetic contribution to colorectal cancer in Newfoundland and Labrador based on family history and tumour molecular analyses for an incident cohort. Masters thesis, Memorial University of Newfoundland.

[English] PDF (Migrated (PDF/A Conversion) from original format: (application/pdf)) - Accepted Version 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. Download (25MB) [English] PDF - Accepted Version 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. (Original Version)

Abstract

Background and Purpose: Colorectal cancer (CRC) is an insidious cancer associated with significant morbidity and mortality. In Canada, it is the second leading cause of cancer death. Newfoundland and Labrador has the highest rate of CRC of all ten Canadian provinces and is ideal for examining founder effects and studying incidence of hereditary disease in what is essentially a closed community. Family history is the strongest risk factor for this disease. Inherited deleterious variants in the mismatch repair (MMR) genes play a critical role in the development of some cases, but families exist who have a family history consistent with autosomal dominant inheritance and no known predisposing genes (Familial colorectal cancer type X, FCCTX). The aim of this study is to determine the genetic basis of CRC in Newfoundland and Labrador, defined by family history, molecular pathology of the CRC and molecular genetics, in an incident cohort of CRC cases occurring in the population during one year. -- Methods: A study population of 262 consecutively diagnosed CRC cases from the Newfoundland population were identified and following application of the recruitment protocol 148 participants, 144 families, completed the study. Eligible probands were contacted for consent and with this permission tumour blocks were obtained. Detailed family histories were obtained and risk classified. Tests of microsatellite stability and immunohistochemistry for mismatch repair proteins in tumour blocks were performed. Cancer phenotypes in family members of patients with CRC were compared in various high risk groups. -- Results: 12.5% of families (n=18) were classified as high risk according to Amsterdam criteria (AC) and Age and Cancer modified Amsterdam criteria (ACMAC). An additional 33.3% fulfilled the revised Bethesda guidelines for intermediate risk classification and 53.5% were low risk. Fifteen (10.9%) families demonstrated microsatellite instability with thirteen (86.7%) of these having a corresponding deficiency in mismatch repair proteins. Eleven of the fifteen high risk families (61.1%) were microsatellite stable (MSS) and had no mismatch repair protein deficiency and family history was consistent with FCCTX or age modified FCCTX. FCCTX family members had a lower frequency of both CRC and Lynch syndrome associated cancers as well as a later age of cancer onset compared to possible Lynch syndrome. -- Conclusions: The incidence of CRC with high or intermediate risk family history is high in Newfoundland and Labrador. Families with a history consistent with autosomal dominant disease occurred in 12.5%; possible Lynch syndrome was suspected in a minority (35%) of these families, and FCCTX/age modified FCCTX in the majority. Phenotype differences exist between FCCTX and suspected LS families in both age of onset and cancer frequency among relatives. Opportunity for novel gene discovery exists because the molecular genetic basis for most of those with familial CRC was not determined.

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