The history of families at-risk for hereditary breast and ovarian cancer: what are the impacts of genetic counseling and testing?

Introduction: Cancer Genetic Counseling (CGC) and genetic testing (GT) assume a paramount role for hereditary cancer predisposition syndrome families. We assessed the effects of CGC and GT on women affected by cancer who are at risk for hereditary breast and ovarian cancer predisposition syndrome (HBOC). Methods: This study encompasses four time points: before the CGC session, after the CGC session when blood is drawn for GT, after disclosure of GT results, and six months following disclosure of GT results. The impacts of CGC and GT were assessed using psychosocial questionnaires. Additionally, a pedigree, genogram, and ecomap were constructed through a semistructured interview. Results: A total of sixty women were included in the study. Most participants considered their perception of cancer risk to be equivalent to that of the general population, even among those with pathogenic variants. An increased perception of breast and ovarian cancer risks was associated with a heightened inclination toward religious engagement as a coping mechanism. Patients carrying variants of uncertain significance expressed greater concerns about developing another cancer compared to those who had BRCA1 and BRCA2 wild type or pathogenic variants. Qualitative analysis of the genograms and ecomaps demonstrated that the CGC/GT processes facilitate communication within families. The genogram analyses revealed the impact of CGC and GT processes on families at risk for hereditary cancer. Changes in some family relationships were observed, and an improvement in communication was noted following the GT process. Discussion: These findings can assist healthcare professionals considering a personalized approaches in clinical practice.

Cost-Effectiveness of BRCA 1/2 Genetic Test and Preventive Strategies: Using Real-World Data From an Upper-Middle Income Country.

Although BRCA1/2 genetic testing in developed countries is part of the reality for high-risk patients for hereditary breast and ovarian cancer (HBOC), the same is not true for upper-middle-income countries. For that reason, this study aimed to evaluate whether the BRCA1/2 genetic test and preventive strategies for women at high risk for HBOC are cost-effective compared to not performing these strategies in an upper-middle-income country. Adopting a payer perspective, a Markov model with a time horizon of 70 years was built to delineate the health states for a cohort of healthy women aged 30 years that fulfilled the BRCA1/2 testing criteria according to the guidelines. Transition probabilities were calculated based on real-world data of women tested for BRCA1/2 germline mutations in a cancer reference hospital from 2011 to 2020. We analyzed 275 BRCA mutated index cases and 356 BRCA mutation carriers that were first- or second-degree relatives of the patients. Costs were based on the Brazilian public health system reimbursement values. Health state utilities were retrieved from literature. The BRCA1/2 genetic test and preventive strategies result in more quality-adjusted life years (QALYs) and costs with an incremental cost-effectiveness ratio of R$ 11,900.31 (U$ 5,504.31)/QALY. This result can represent a strong argument in favor of implementing genetic testing strategies for high-risk women even in countries with upper-middle income, considering not only the cancer prevention possibilities associated with the genetic testing but also its cost-effectiveness to the health system. These strategies are cost-effective, considering a willingness-to-pay threshold of R$ 25,000 (U$ 11,563.37)/QALY, indicating that the government should consider offering them for women at high risk for HBOC. The results were robust in deterministic and probabilistic sensitivity analyses.

Using Co-segregation and Loss of Heterozygosity Analysis to Define the Pathogenicity of Unclassified Variants in Hereditary Breast Cancer Patients.

The use of gene panels introduces a new dilemma in the genetics field due to the high frequency of variants of uncertain significance (VUS). The objective of this study was to provide evidence that may help in the classification of these germline variants in terms of their clinical impact and association with the disease in question. A total of 52 unrelated women at-risk for HBOC and negative for BRCA1/BRCA2 pathogenic variants were evaluated through a gene panel comprising 14 breast and/or ovarian cancer susceptibility genes. Of the 453 germline variants identified, 15 variants (classes 3, 4, and 5) in the ATM, BRIP1, CHEK2, MRE11A, MUTHY, PALB2, RAD50, and RAD51C genes were evaluated via databases, co-segregation studies and loss of heterozygosity in the tumor. The co-segregation analysis allowed the establishment of an association with the presence of variants and the risk of cancer for variant c.316C>T in the BRIP1 gene. Four variants of uncertain significance showed loss of heterozygosity in the tumor (ATM c.4709T>C; CHEK2 c.1036C>T; PALB2 c.1001A>G, and RAD50 c.281T>C), which is an indication of pathogenicity. Thus, the present study provides novel evidence that favors the association of variants in moderate-risk genes with the development of hereditary breast cancer.

Genetic alterations detected by comparative genomic hybridization in BRCAX breast and ovarian cancers of Brazilian population.

BACKGROUND: About 5-10% of breast/ovarian cancers are hereditary. However, for a large proportion of cases (around 50%), the genetic cause remains unknown. These cases are grouped in a separated BRCAX category. The aim of this study was to identify genomic alterations in BRCA1/BRCA2 wild-type tumor samples from women with family history strongly suggestive of hereditary breast/ovarian cancer. RESULTS: A cohort of 31 Brazilian women was included in the study. Using the GISTIC algorithm, we identified 20 regions with genomic gains and 31 with losses. The most frequent altered regions were 1q21.2, 6p22.1 and 8p23.3 in breast tumors and Xq26 and Xp22.32-22.31 among the ovarian cancer cases. An interesting association identified was the loss of 22q13.31-13.32 and the presence of ovarian cancer cases. Among the genes present in the frequently altered regions, we found FGFR1, NSMCE2, CTTN, CRLF2, ERBB2, STARD3, MIR3201 and several genes of RAET and ULBP family. CONCLUSIONS: In conclusion, our results suggest that alterations on chromosomes 1, 6, 8 and X are common on BRCAX tumors and that the loss on 22q can be associated with the presence of ovarian cancer. METHODS: DNA copy number alterations were analyzed by 60K array comparative genomic hybridization in breast and ovarian FFPE tumors.

Genetic and epigenetic characterization of the BRCA1 gene in Brazilian women at-risk for hereditary breast cancer.

This study aimed to characterize women at-risk for hereditary BC regarding their clinical and molecular characteristics (mutation and methylation in the BRCA1 gene) and correlate the gene expression levels with histopathological, clinical and family history information. BRCA1 real time qPCR was performed to evaluate methylation status and gene expression. The study included 88 women grouped according to the BRCA1 mutational status: 23 BRCA1 mutated, 22 with a Variant of Unknown Significance (VUS) in BRCA1 and 43 BRCA1 WT. Most BRCA1 mutated tumors were triple negative (69.6%) and had histologic grade III (61.0%). Patients with VUS/WT BRCA1 were predominantly of luminal B subtype with histological grades I and II. Regarding the methylation profile, BRCA1 hypermethylation was observed in only two patients (both WT) and none had association with pathogenic BRCA1 mutation. In one patient methylation was present in both, tumor and normal tissues. Hypermethylated tumors had ductal histology, negativity for ER and occurred in < 50 years patients. Gene expression profile showed in all groups lower BRCA1 mRNA levels in tumor tissue compared to the adjacent breast tissue, thereby indicating the loss/decrease of gene function. No association was found between the levels of BRCA1 gene expression and family history of cancer. In summary, our findings suggested that methylation at the BRCA1 gene is not the "second" event in the development of BC in patients with germline mutations in BRCA1 and, although rare, BRCA1 epimutations can constitute an explanation for a fraction of HBOC families.