title: Molecular genetics improves the management of hereditary non-polyposis colorectal cancer.
abstract: BACKGROUND
  The syndrome of hereditary non-polyposis colorectal cancer (HNPCC) can be diagnosed fairly accurately using clinical criteria and a family history. Identifying HNPCC helps to prevent large-bowel cancer, or allows cancer to be treated at an early stage. Once the syndrome has been diagnosed a family member's risk can be judged approximately from a family tree, or it can now be predicted accurately if the causative mutation is known.
  
  
  OBJECTIVE
  This study involved attempts to improve the management of a family with HNPCC over a period of 10 years. Clinical diagnostic criteria, colonoscopic surveillance, surgical treatment, genetic counselling, molecular genetic research, and finally predictive genetic testing were applied as they evolved during this time.
  
  
  METHODS
  A rural general practitioner first noted inherited large-bowel cancer in the family and began screening subjects as they presented, using rigid sigmoidoscopy at the local hospital. At the time that the disorder was recognised as being HNPCC (1987), screening by means of colonoscopy at our university hospital was aimed primarily at first-degree relatives of affected individuals. After realising how many were at risk, screening was brought closer to the family. A team of clinicians and researchers visited the local hospital to identify and counsel those at risk and to perform screening colonoscopy. Family members were recruited for research to find the gene and its mutation that causes the disease, to develop an accurate predictive test and to reduce the number of subjects undergoing surveillance colonoscopies.
  
  
  RESULTS
  There are approximately 500 individuals in this family. In the 10 years of this study the number of subjects who have been counselled for increased genetic risk or who have requested colonoscopic surveillance for HNPCC in this kindred has increased from 20 to 140. After the causative mutation was found in the hMLH1 gene on chromosome 3, a test for it has reduced the number of subjects who need screening colonoscopy by over 70%. A protocol has been devised to inform family members, to acquire material for research in order to provide genetic counselling for (pre-test and post-test) risk, and to test for the mutation. Eventually, identifying those with the mutation should focus surveillance accurately.
  
  
  CONCLUSIONS
  The benefits of restricting screening to subjects with the mutation that causes colorectal cancer and of performing operations to prevent cancer are hard to measure accurately. However, it is likely that at least half the family members will be able to avoid colonoscopic screening, some deaths from cancer should be prevented, and the cost of preventing and treating cancer in the family should fall substantially.
authors.affiliation: Department of Human Genetics, Groote Schuur Hospital.
authors.forename: R S
authors.initials: RS
authors.lastname: Ramesar
authors.forename: M V
authors.initials: MV
authors.lastname: Madden
authors.forename: R
authors.initials: R
authors.lastname: Felix
authors.forename: C J
authors.initials: CJ
authors.lastname: Harocopos
authors.forename: C A
authors.initials: CA
authors.lastname: Westbrook
authors.forename: G
authors.initials: G
authors.lastname: Jones
authors.forename: J P
authors.initials: JP
authors.lastname: Cruse
authors.forename: P A
authors.initials: PA
authors.lastname: Goldberg
mesh_terms: D000328:Adult; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis; D016099:Endoscopy, Gastrointestinal; D005260:Female; D005817:Genetic Counseling; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008967:Molecular Biology / Q000379:methods*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012306:Risk; D012424:Rural Population; D013019:South Africa
chemical_list: D004273:DNA, Neoplasm