title: Aetiology of colorectal cancer and relevance of monogenic inheritance.
abstract: OBJECTIVE
  Although diet and lifestyle are associated with the development of colorectal malignancies, the only clearly identified aetiological factors in colorectal cancer are inheritance (hereditary non-polyposis colorectal cancer (HNPCC) and familial polyposis), inflammatory bowel diseases, papillomavirus, and acquired immunodeficiency syndrome (AIDS). Our aim was to determine what proportion of colorectal neoplasms could be attributed to these specific factors.
  
  
  METHODS
  Data from a colorectal cancer registry were analysed over a 15 year period, during which nearly 2500 cases were recorded. In patients with suspected HNPCC, microsatellite instability and immunohistochemical expression of proteins encoded by the main DNA mismatch repair genes were assessed. In families with unstable neoplasms, constitutional mutations of the mismatch repair genes hMSH2, hMLH1, and hMSH6 were evaluated by single strand conformation polymorphism analysis and sequencing.
  
  
  RESULTS
  Inflammatory bowel diseases, familial polyposis, and AIDS were rare causes of colorectal cancer (three, three, and one case, respectively). Anal squamous carcinoma developed in 27 patients (1.0%) and could be attributed to papillomavirus infection. In 58 patients (from 34 families) a clinical diagnosis of HNPCC was established (2.4%). In total, cases with a known aetiology were 92 (3.7% of all patients). Microsatellite instability was detected in 15 cancers from HNPCC families, and germline mutations in six families (12 patients, 0.5% of the total). Families with unstable tumours, with or without mutations, were clinically similar, suggesting the involvement of the mismatch repair system even when mutations were not detected.
  
  
  CONCLUSIONS
  The study suggests that the aetiology of colorectal malignancies remains elusive in the large majority of cases. Among specific causes, HNPCC represents the most frequent. However, with a population based approach, constitutional mutations of the main genes involved in HNPCC can be detected in only 20% of cases.
authors.affiliation: Dipartimento di Medicine e Specialità Mediche, Università di Modena e Reggio Emilia, Modena, Italy. deleon@unimo.it
authors.forename: M
authors.initials: M
authors.lastname: Ponz de Leon
authors.forename: P
authors.initials: P
authors.lastname: Benatti
authors.forename: F
authors.initials: F
authors.lastname: Borghi
authors.forename: M
authors.initials: M
authors.lastname: Pedroni
authors.forename: A
authors.initials: A
authors.lastname: Scarselli
authors.forename: C
authors.initials: C
authors.lastname: Di Gregorio
authors.forename: L
authors.initials: L
authors.lastname: Losi
authors.forename: A
authors.initials: A
authors.lastname: Viel
authors.forename: M
authors.initials: M
authors.lastname: Genuardi
authors.forename: G
authors.initials: G
authors.lastname: Abbati
authors.forename: G
authors.initials: G
authors.lastname: Rossi
authors.forename: M
authors.initials: M
authors.lastname: Menigatti
authors.forename: I
authors.initials: I
authors.lastname: Lamberti
authors.forename: G
authors.initials: G
authors.lastname: Ponti
authors.forename: L
authors.initials: L
authors.lastname: Roncucci
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D000328:Adult; D017677:Age Distribution; D000368:Aged; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D015212:Inflammatory Bowel Diseases / Q000150:complications; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000150:complications; D010375:Pedigree; D012042:Registries; D016019:Survival Analysis
chemical_list: D004273:DNA, Neoplasm