Genotype-phenotype correlation in 99 familial adenomatous polyposis patients: A prospective prevention protocol

Abstract

Background: Familial adenomatous polyposis (FAP) is a syndrome caused by germline pathogenic variants in the tumor suppressor gene adenomatous polyposis coli (APC). Identification of APC pathogenic variants sites and the genotype-phenotype correlation are important for characterizing, monitoring, and treating members of affected families. The aim of this study was to correlate genotype-phenotype of Brazilian individuals carrying APC pathogenic germline variants and that have FAP.

Methods: The polyposis phenotype of 99 individuals from 35 families between July 2013 and December 2014 were prospectively evaluated based on the InSIGHT polyposis staging classification. Seven extra-colonic manifestations were assessed and the clinical manifestations correlated with the APC genotype.

Results: The age of the study participants ranged from 12 to 67 years (median of 29 years). Twenty-six APC pathogenic variants were identified. Fifty-five cases harbored nonsense pathogenic variants (55.6%). Frameshift alterations were noted in 39 cases (39.4%). Aberrant splicing was noted in 1 case (1%). Rearrangements were observed in 3 cases (3%). An association between nonsense variants and rearrangement was noted in 1 case (1%). The genotype-phenotype correlation analysis led the identification of classic FAP in 94 cases (94.9%). Profuse polyposis was identified in 5 cases (5.1%). Thirty-six cases were diagnosed with cancer of which 29 cases (80.6%) were colorectal cancer, 1 case (2.7%) was brain cancer, 4 cases (11.2%) were papillary thyroid cancer, and 2 cases (5.5%) were stomach cancer. The extra-colonic manifestations included 9 individuals with desmoids tumors, 10 with osteomas, and 9 with congenital hypertrophy of the retinal pigment epithelium.

Conclusions: The genotype-phenotype correlation in Brazilian individuals with FAP revealed specific findings not previously reported for other cohorts, demonstrating the relevance of knowledge regarding the variable pathogenic variants and clinical presentation in different populations for adequate individual clinical management of patients harboring this medical condition.

Keywords: adenomatous polyposis coli; colorectal neoplasms; genotype; germline pathogenic variants; phenotype.