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

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.

Identification of hereditary cancer in the general population: development and validation of a screening questionnaire for obtaining the family history of cancer.

One of the challenges for Latin American countries is to include in their healthcare systems technologies that can be applied to hereditary cancer detection and management. The aim of the study is to create and validate a questionnaire to identify individuals with possible risk for hereditary cancer predisposition syndromes (HCPS), using different strategies in a Cancer Prevention Service in Brazil. The primary screening questionnaire (PSQ) was developed to identify families at-risk for HCPS. The PSQ was validated using discrimination measures, and the reproducibility was estimated through kappa coefficient. Patients with at least one affirmative answer had the pedigree drawn using three alternative interview approaches: in-person, by telephone, or letter. Validation of these approaches was done. Kappa and intraclass correlation coefficients were used to analyze data's reproducibility considering the presence of clinical criteria for HCPS. The PSQ was applied to a convenience sample of 20,000 women of which 3121 (15.6%) answered at least one affirmative question and 1938 had their pedigrees drawn. The PSQ showed sensitivity and specificity scores of 94.4% and 75%, respectively, and a kappa of 0.64. The strategies for pedigree drawing had reproducibility coefficients of 0.976 and 0.850 for the telephone and letter approaches, respectively. Pedigree analysis allowed us to identify 465 individuals (24.0%) fulfilling at least one clinical criterion for HCPS. The PSQ fulfills its function, allowing the identification of HCPS at-risk families. The use of alternative screening methods may reduce the number of excluded at-risk individuals/families who live in locations where oncogenetic services are not established.