title: Hereditary colorectal cancer: A clinical and molecular genetic study
Creators: name: Whitelaw, Stuart Charles
Publisher: name: University of Glasgow
Year: 1996
Subjects: subject: Oncology, genetics.

description: The general aim of this thesis was to advance our understanding of the genetics of colorectal cancer. The specific aims were 1) to assess the psychological impact of familial adenomatous polyposis and patient attitude to predictive DNA testing, 2) to assess the prognostic value of allele loss in colorectal cancer and 3) to assess the effectiveness of a family cancer clinic for the targeted screening of colorectal cancer. Attitudes to predictive DNA testing and the psychological impact of familial adenomatous polyposis (FAP) were documented in 62 affected adults. In the majority of cases, FAP, appeared to have a fairly minimal impact on the everyday life of the patient. However, in a significant minority (20%), a diagnosis of FAP had a devastating effect on psychological well being. Factors which might be important include a previous unpleasant experience with an ileostomy, a history of cancer death within the family, a poor understanding of the mode of transmission of FAP and a perceived delay in diagnosis. With respect to patient views on prenatal testing and termination of pregnancy for FAP, fifteen (24%) of those questioned stated that they would proceed to termination of pregnancy if a prenatal test indicated that the unborn baby was affected. Six (10%) of people who had refrained from having children for fear of passing on the polyposis gene felt that the arrival of prenatal testing would enable them to consider planning a family. The majority of patients (93%) said that they would like their children tested by DNA analysis at birth or infancy, but felt that 10-12 years was the most appropriate time to discuss the diagnosis with the child. The frequency of allele loss at the APC, P53, Nm23 and DCC gene loci was investigated in a panel of 63 colorectal cancer specimens by Southern blotting analysis and correlation with prognosis studied. Sixty-percent of the specimens studied, exhibited allele loss for at least one genetic marker ( 52% at the P53 locus, 38% at the APC locus and 36% at the DCC locus). No allele loss was found at the Nm 23 locus. Univariate analysis found that allele loss on chromosome 17p was related to prognosis ( P &lt; 0.02), although a multivariate analysis, including other accepted prognostic indicators for colorectal cancer, failed to support this association. The results of screening individuals referred to the Family Cancer Clinic at St Mark's Hospital, London, are described. Colonoscopy was performed in 644 asymptomatic individuals (from 436 families) with a family history of colorectal cancer over a six year period. Families were subdivided according to family history and sixty nine (15.8%) of the families fulfilled the Amsterdam criteria for the hereditary nonpolyposis colorectal cancer syndromes (HNPCC). Seven cases of colorectal cancer were diagnosed at an average age of 49 years; six at Dukes' stage A and one at stage C; four in HNPCC families. One hundred and forty four (22.4%) subjects had one or more adenomas. The prevalence of adenomas in the subjects from Amsterdam criteria families was 34 of 127 (26.8%) compared with 110 of 517 (21.3%) in non - Amsterdam criteria families. Men were twice as likely to develop adenomas as women, and the prevalence of adenomas increased in both sexes with age; the odds ratio (O.R.) increasing approximately two-fold for each decade (p or = 2 versus 1) affected by colorectal cancer or adenomas was a highly significant independent variable associated with a an increased risk of adenoma development. As part of this project, a very large kindred, St Marks' Family 96, was identified, which appears to have an autosomal dominant predisposition to an atypical polyposis syndrome and colorectal cancer. This syndrome has been called the "Hereditary Mixed Polyposis Syndrome" (HMPS) by the author. Affected individuals usually present in the fourth decade with symptomatic polyps or cancer. Although adenomatous and hyperplastic polyps occur in affected members, the characteristic lesion is an atypical juvenile polyp. Some individuals have developed polyps of more than one type, and individual polyps may have mixed histological features. Typically, fewer than 15 polyps are found at colonoscopy, and there is no extracolonic disease associated with the development of polyps. St Mark's Family 96 consist of 10 second generation, 35 third generation, 63 fourth generation and 42 fifth generation individuals. All surviving members are derived from the third, fourth and fifth generations, and updated clinical information has been obtained in 71 patients over the age of 21 years. Thirty three members (13 females, 19 males) are known to have developed either colorectal cancer or polyps. A genetic linkage study was performed on this family using 77 genetic markers spanning the genome. Data did not support linkage to the APC locus or any of the loci responsible for HNPCC. The most positive LOD score (0.69) was obtained with the marker D6S44 which maps to chromosome 6p21-qter. Although the gene responsible for HMPS was not localised within the time period of this project, a subsequent linkage study found significant two-point LOD scores for linkage between HMPS and the D6S283 locus. Analysis of recombinants and multipoint linkage analysis suggests that the gene responsible for HMPS lies in a 4-cM interval containing the D8S283 locus and flanked by markers D6S468 and D6S301.