Hereditary Breast Cancer in the Brazilian State of Ceará (The CHANCE Cohort): Higher-Than-Expected Prevalence of Recurrent Germline Pathogenic Variants.

Purpose: There is a significant lack of epidemiological data on hereditary cancer in Northeast Brazil. This is the largest study on the prevalence and mutational spectrum of cancer predisposition genes conducted in this region and the first in the State of Ceará. Methods: Patients ≥18 years of age that were referred to CHANCE (Grupo de Câncer Hereditário do Ceará) from March 2014 to December 2020 with testing criteria for breast cancer susceptibility genes according to NCCN v.1.2021 were eligible to participate. The inclusion of patients was limited to one individual per family and to those born in the State of Ceará. All patients underwent a hereditary cancer panel testing with at least 30 genes. Results: A total of 355 patients were included, and 97 (27.3%) carried a P/LP germline variant in 18 different genes. Among the 97 P/LP carriers, BRCA1 (31, 31.9%) and BRCA2 (25, 25.7%) were the most frequently mutated genes, followed by PALB2 (10, 10.3%), CHEK2 (7, 7.2%) and ATM (4, 4.1%). A small number of recurrent variants (detected in three or more individuals) in BRCA1, BRCA2, CHEK2 and ATM represented the majority of the P/LP variants described in this cohort. Conclusion: In this cohort, the prevalence of L/PL was high, particularly involving the BRCA1, BRCA2, PALB2, CHEK2 and ATM genes and, to a lesser extent than expected, the TP53 gene. A high frequency of recurrent variants was also observed, for which further and larger analyses should clarify the presence of any possible founder effect. Characterizing the mutational profile of cancer predisposition genes in diverse populations may contribute to cancer prevention and therapeutic management.

Cancer risk-reducing surgery: Brazilian society of surgical oncology guideline part 1 (gynecology and breast).

BACKGROUND: Risk-reducing operations are an important part of the management of hereditary predisposition to cancer. In selected cases, they can considerably reduce the morbidity and mortality associated with cancer in this population. OBJECTIVES: The Brazilian Society of Surgical Oncology (BSSO) developed this guideline to establish national benchmarks for cancer risk-reducing operations. METHODS: The guideline was prepared from May to December 2021 by a multidisciplinary team of experts to discuss the surgical management of cancer predisposition syndromes. Fourteen questions were defined and assigned to expert groups that reviewed the literature and drafted preliminary recommendations. Following a review by the coordinators and a second review by all participants, the groups made final adjustments, classified the level of evidence, and voted on the recommendations. RESULTS: For all questions including risk-reduction bilateral salpingo-oophorectomy, hysterectomy, and mastectomy, major agreement was achieved by the participants, always using accessible alternatives. CONCLUSION: This and its accompanying article represent the first guideline in cancer risk reduction surgery developed by the BSSO, and it should serve as an important reference for the management of families with cancer predisposition.

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.

Caracterização de pacientes submetidos a aconselhamento genético para síndromes de câncer hereditário no Ceará e análise de modificadores de penetrância na síndrome de Li-Fraumeni / Description of patientes submitted to genetic couseling for hereditary cancer syndromes in Ceará and analysis of penetrance modifiers in Li-fraumeni syndrome

O diagnóstico de pacientes portadores de síndromes de predisposição hereditária ao câncer (SPHC) possibilita a abordagem diferenciada de rastreamento e prevenção e fornece valiosas informações prognósticas e preditivas de resposta a tratamentos oncológicos. Objetivos: Os objetivos deste estudo foram introduzir a assistência em oncogenética no Ceará e caracterizar a população atendida. Também pretendemos, em colaboração com o National Cancer Institute (NCI/NIH), analisar modificadores de penetrância na Síndrome de Li-Fraumeni (LFS) e o impacto psicológico do diagnóstico desta síndrome nos pacientes acompanhados em São Paulo e no NCI. Resultados: No período de agosto de 2013 a agosto de 2016, 193 pacientescearenses foram submetidos a aconselhamento genético. Em 95 (63%) dos 149 probandos com suspeita clínica de SPHC, foi realizada investigação molecular em 24 (25%) dos casos foram encontradas mutações germinativas patogênicas: 14 em BRCA1 (58%), 6 em BRCA2 (25%), 1 em PALB2 (4%), 1 em NEM1 (4%), 1 em R ET(4%) e 1 em NF1 (4%). Entre as pacientes cearenses com síndrome de câncer de mama e ovário hereditários (HBOC), houve um padrão recorrente de mutações, sendo as mais frequentes: c.5074+2T>C (4 probandos) e c.3331_3334delCAAG (5 probandos) em BRCA1, e c.4808delA (4 probandos) em BRCA2. Para a análise de modificadores de penetrância na LFS, foram incluídos 50 pacientes portadores de LFS acompanhados no AC Camargo Cancer Center. A análise psicológica conjunta destes pacientes brasileiros e dos pacientes americanos com diagnóstico de LFS revelou um nível médio de estresse. Conclusão: Este estudo evidenciou uma elevada prevalência de HBOC no Ceará, com mutações germinativas recorrentes nos genes BRCA1/2. O impacto psicológico do diagnóstico de uma SPHC como a LFS não gera um nível elevado de estresse.

Recognizing patients with hereditary predisposition to cancer (HCP) allows targeted efforts in cancer surveillence and prevention, and may also provide important information towards prognosis and response to some systemic oncological treatments. Purpose: The purpose of this study is to introduce genetic counseling in Ceará, characterizing this population, and also, in collaboration with the National Cancer Institute (NCI/NIH), to analyse penetrance modifiers in Li-Fraumeni Syndrome (LFS). Results:Between August 2013 and August 2016, 193 patients from Ceará were included in this study.95 (63%) from the 149 probands with suspected HCP were submitted to molecular investigation and in 24 (25%) germline pathogenic variantswere detected: 14 inBRCA1 (58%), 6 inBRCA2 (25%), 1 inPALB2 (4%), 1 inNEM1 (4%), 1 inR ET(4%) and 1 inNF1 (4%). Among patients with Hereditary Breast and Ovarian Cancer syndrome (HBOC), there was a recurrent pattern of mutations, and the most frequent were: c.5074+2T>C (4 probands) andc.3331_3334delCAAG (5 probands) inBRCA1, andc.4808delA (4 probands) inBRCA2. For the penetrance modifiers analysis in LFS, 50 patients were included, all of them from A.C.Camargo Cancer Center (São Paulo). The joint analysis of Brazilian and American patients revealed that the stress level of this population is medium.Conclusion: This study showed a high prevalence of HBOC among Cearense patients with a pattern of recurrent mutations that need further investigation. After the diagnosis of a high penetrant HCP syndrome like LFS, patients experience median levels of stress.