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.

Family history of cancer in Brazil: is it being used?

In developing countries, low budgets make the issue of integrating genetics into clinical practice a challenge, a situation in which the use of family history (FH) becomes important for patient care, as it is a low cost strategy and a risk assessment tool. The purpose of this study was to review medical records of patients with colorectal cancer (CRC) seen in a public University Hospital and evaluate how often FH of cancer is registered. Initially we searched a database for patients who were seen in our hospital between 2002 and 2004 with the diagnosis of CRC. We found 415 patients, 104 of whom were excluded. A total of 311 charts were reviewed and classified into 3 groups. Group A: no FH documented; group B: FH was documented, but FH of cancer was not collected; and group C: FH of cancer was documented. We also investigated what type of information was recorded, in order to verify if important elements were assessed. Ninety-eight charts (31.5%) were classified in group A, 20 (6.5%) in group B, and 193 (62%) in group C. In addition, we observed that important information regarding affected relatives was not collected in most of the charts. In conclusion, we found that although FH of cancer was recorded in 62% of charts of patients with CRC, information that could be relevant for risk assessment and management of at-risk families was missing. Our findings expose an important problem in health education that could reflect negatively in the quality of medical assistance to individuals at risk for familial cancer.

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.

Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry.

BACKGROUND: There are very few data about the mutational profile of families at-risk for hereditary breast and ovarian cancer (HBOC) from Latin America (LA) and especially from Brazil, the largest and most populated country in LA. RESULTS: Of the 349 probands analyzed, 21.5% were BRCA1/BRCA2 mutated, 65.3% at BRCA1 and 34.7% at BRCA2 gene. The mutation c.5266dupC (former 5382insC) was the most frequent alteration, representing 36.7% of the BRCA1 mutations and 24.0% of all mutations identified. Together with the BRCA1 c.3331_3334delCAAG mutation, these mutations constitutes about 35% of the identified mutations and more than 50% of the BRCA1 pathogenic mutations. Interestingly, six new mutations were identified. Additionally, 39 out of the 44 pathogenic mutations identified were not previously reported in the Brazilian population. Besides, 36 different variants of unknown significance (VUS) were identified. Regarding ancestry, average ancestry proportions were 70.6% European, 14.5% African, 8.0% Native American and 6.8% East Asian. MATERIALS AND METHODS: This study characterized 349 Brazilian families at-risk for HBOC regarding their germline BRCA1/BRCA2 status and genetic ancestry. CONCLUSIONS: This is the largest report of BRCA1/BRCA2 assessment in an at-risk HBOC Brazilian population. We identified 21.5% of patients harboring BRCA1/BRCA2 mutations and characterized the genetic ancestry of a sample group at-risk for hereditary breast cancer showing once again how admixed is the Brazilian population. No association was found between genetic ancestry and mutational status. The knowledge of the mutational profile in a population can contribute to the definition of more cost-effective strategies for the identification of HBOC families.