Genotype–phenotype correlation in colorectal polyposis

Newton KF, Mallinson EKL, Bowen J, Lalloo F, Clancy T, Hill J, Evans DGR. Genotype–phenotype correlation in colorectal polyposis. 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.