title: Genotype-phenotype correlation in colorectal polyposis.
abstract: Familial adenomatous polyposis (FAP) has been divided into three clinical subtypes: mild, classical and severe. This study aimed to investigate for a correlation between genotype and phenotype. A codon-specific survival difference is unknown. A retrospective longitudinal study of 492 patients on the Manchester Polyposis Registry was conducted. Patients were grouped according to genotypes: 0, unknown mutation; 1, adenomatous polyposis coli (APC) 0-178 (and 312-412 of exon 9); 2, APC >1550; 3, APC 179-1249; 4, APC 1250-1549; and 5, MutYH. Date of onset of polyposis, incidence of colorectal cancer (CRC), survival and actuarial time to surgery were calculated. Median age of onset of polyposis for genotype 0 was 20.3 years, genotype 1 35.6 years, genotype 2 32.2, genotype 3 15.9 years, and genotype 4 14.8 years (p < 0.0001). Age of onset of CRC was similar between genotypes. Median survival for genotype 0 was 56.6 years, genotype 1 74.9 years, genotype 2 61.0 years, genotype 3 63.0 years, genotype 4 48.1 years, and genotype 5 69.7 years (p = 0.003). This survival difference was also seen when patients who underwent screening and those who did not were analysed separately. Survival in the screened population was 53.9 years in genotype 4 and 72.9 years in genotype 3. Patients with genotype 4 (APC 1249-1549) have a significantly worse survival despite screening and early prophylactic surgery. This analysis supports a genotype-phenotype correlation. Patients with a mutation APC 1249-1549 develop polyposis at an early age and have a worse survival. Patients with a mutation APC 0-178 or 312-412 develop polyposis later and have an improved survival. This survival difference has not previously been documented.
authors.affiliation: Department of General Surgery, Manchester Royal Infirmary, Manchester, UK. katynewton2002@yahoo.co.uk
authors.forename: K F
authors.initials: KF
authors.lastname: Newton
authors.forename: E K L
authors.initials: EK
authors.lastname: Mallinson
authors.forename: J
authors.initials: J
authors.lastname: Bowen
authors.forename: F
authors.initials: F
authors.lastname: Lalloo
authors.forename: T
authors.initials: T
authors.lastname: Clancy
authors.forename: J
authors.initials: J
authors.lastname: Hill
authors.forename: D G R
authors.initials: DG
authors.lastname: Evans
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000453:epidemiology / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D015994:Incidence; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012189:Retrospective Studies; D013534:Survival