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Genotype–phenotype correlation in colorectal polyposis


Katy Newton, Department of Medical Genetics, 6th Floor, St. Mary's Hospital, Oxford Road, M13 9LW Manchester, UK.
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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.