Cancer Risk Factors in Southern Brazil: Report of a Comprehensive, Matched Case-Control Study.

PURPOSE: To evaluate cancer risk factors among cancer cases and controls from Southern Brazil, to analyze a multigene hereditary panel testing (MGPT, 26 genes) for breast cancer (BC) and colorectal cancer (CCR) cases diagnosed age younger than 50 years and to characterize them for hereditary cancer syndrome (HCS) phenotypes. METHODS: A case-control (matched by age group and sex) study was conducted on regional cancer. Data on exposure factors and first-/second-degree family history of cancer (1/2FHC) were collected. The MGPT was performed using Illumina next-generation sequencing technology. RESULTS: A total of 1,007 cases and 1,007 controls were included. The most frequent cancers were BC (n = 311), CCR (n = 147), prostate (n = 132), and lung cancers (n = 89). It was independently associated with cancer, 1/2FHC, tobacco consumption (TC), pesticide exposure (PE), solvent/glue exposure, and BMI <24. BC was associated with 1/2FHC, TC, and hormone replacement therapy use; CCR with 1/2FHC, TC, and BMI <24; prostate cancer with 1/2FHC, TC, and alcohol consumption; and lung cancer with 1/2FHC, TC, PE, and BMI <24. MGPT identified pathogenic/likely pathogenic mutations in 24 (32%) women with BC and in three (18%) women and four (24%) men diagnosed with CCR at under 50 years. Among the tested patients under 50 years with diagnosed BC and CCR, 98.6% and 97% present criteria for HCS, respectively. CONCLUSION: This study confirmed the association of several factors associated with BC, CCR, prostate, and lung cancers and reinforced the importance of evaluating FHC and genetic testing, especially for patients under 50 years with diagnosed BC or CCR. A better understanding of population-specific cancer risk factors builds on sustainable data for developing prevention strategies. These efforts increase the commitment to early detection and surveillance.

TP53 variants of uncertain significance: increasing challenges in variant interpretation and genetic counseling.

Li-Fraumeni syndrome (LFS) and Li-Fraumeni Like (LFL) are autosomal dominant cancer predisposition syndromes caused by pathogenic germline variants in the TP53 gene. Recent studies have shown that the incorporation of next-generation sequencing by using multigene panels in clinical practice has resulted in the frequent identification of variants of uncertain significance (VUS). Given that there is no established medical management for VUS carriers, the identification of these variants may cause confusion and anxiety for both patients and practitioners. Herein, we aimed to verify VUS frequency and review VUS classification and interpretation in 1844 patients submitted for comprehensive germline TP53 testing independent of clinical criteria. Variant characterization was done assessing clinical information whenever available, variant frequency in population databases, pathogenicity predictions using in silico tools and previous functional studies. All variants were classified based on the guidelines proposed by the American College of Medical Genetics and Genomics (2015) and by the Sherloc framework (2017). Of the twelve VUS (0.65%) identified in TP53, two were classified as likely pathogenic and two were classified as likely benign after re-evaluation, potentially resulting in significant management modification for the proband and relatives. This report cases highlights the challenges and impact of TP53 variant interpretation especially when there is no clear LFS/LFL phenotype.

Screening and characterization of BRCA2 c.156_157insAlu in Brazil: Results from 1380 individuals from the South and Southeast.

Portuguese immigration to Brazil occurred in several waves and greatly contributed to the genetic composition of current Brazilian population. In this study, we evaluated the frequency of a Portuguese founder Alu insertion in BRCA2 exon 3 (c.156_157insAlu) among individuals fulfilling Hereditary Breast and Ovarian Cancer (HBOC) syndrome criteria in 1,380 unrelated families originated from three distinct Brazilian States. We identified the c.156_157insAlu BRCA2 mutation in nine (9/1,380; 0.65%) probands analised. In carrier probands, European ancestry had the highest proportion (80%), followed by the African (10%) and Amerindian and in most families with the rearrangement, haplotype analyses were compatible with the Portuguese ancestral haplotype. In conclusion, the present study reports a low albeit relevant frequency of the Portuguese BRCA2 founder mutation c.156_157insAlu in Brazilian patients at-risk for HBOC Brazilian population.

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

TP53 p.Arg337His germline mutation prevalence in Southern Brazil: Further evidence for mutation testing in young breast cancer patients.

Premenopausal breast cancer (BC) is a core tumor of Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) Syndromes, predisposition disorders caused by germline mutations in TP53 gene. In the Southern and Southeastern regions of Brazil, a specific TP53 germline mutation, c.1010G>A (p.Arg337His), was identified at a population frequency of 0.3%, the highest value ever described for a TP53 germline variation. In Brazilian BC patients, carrier frequency can vary from 0.5% to 8.7%. The current study assessed carrier frequency by genotyping TP53 c.1010G>A in 2 BC groups: 1) 315 patients unselected for age of diagnosis and family history (FH) and 2) 239 patients diagnosed before 46 years and without Chompret criteria for LFS or LFL. One carrier was identified in group 1 (0.3%; CI 95% 0.1-1.76%) and six carriers in group 2 (2.5%; CI 95% 0.93-5.39%). The frequencies differed significantly between groups (p = 0.04). The mutation carrier frequency observed in group 2 could justify mutation testing in BC patients diagnosed before 46 years and without Chompret criteria for LFS or LFL. Further studies in larger samples of BC patients of different ages and regions of the country are necessary to provide more definitive TP53 p.Arg337His carrier frequencies in different scenarios.

Adherence to Treatment of Phenylketonuria: A Study in Southern Brazilian Patients

Abstract Introduction: Phenylketonuria (PKU) is caused by the deficient activity of phenylalanine hydroxylase. Aim: To identify the factors associated with treatment adherence among patients with PKU seen at a southern Brazil reference center. Methodology: A cross-sectional, outpatient-based study including 56 patients with PKU (median age, 12 years) for whom a Phe-restrict diet plus specific metabolic formula have been prescribed. Patients were considered adherent or nonadherent depending on the median phenylalanine concentration for the 12 months prior to study and target levels of phenylalanine for each age range (<13 years = ≤360 µmol/L; ≥13 years = ≤900 µmol/L). Data were collected through a review of patient's medical records and a set of interviews with patients and their relatives. Results: Eighteen patients (32.1%; ≥13 years, 11) were classified as treatment adherent. Among all factors analyzed, only mental retardation, living with parents, and level of maternal education were associated with adherence to treatment. Conclusion: Our findings reinforce the importance of the family as promoting factor for treatment adherence.