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The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients.

ABSTRACT: Hereditary cancer risk syndromes are caused by germline variants, commonly in tumor suppressor genes. Most studies on hereditary cancer have been conducted in white populations. We report the largest study in Brazilian individuals with multiple ethnicities. We genotyped 1682 individuals from all country regions with Next-generation sequencing (NGS) panels. Most were women with a personal/family history of cancer, mostly breast and ovarian. We identified 321 pathogenic/likely pathogenic (P/LP) variants in 305 people (18.1%) distributed among 32 genes. Most were on BRCA1 and BRCA2 (129 patients, 26.2% and 14.3% of all P/LP, respectively), MUTYH (42 monoallelic patients, 13.1%), PALB2 (25, 7.8%), Lynch syndrome genes (17, 5.3%), and TP53 (17, 5.3%). Transheterozygosity prevalence in our sample was 0.89% (15/1682). BRCA1/BRCA2 double heterozygosity rate was 0.78% (1/129) for BRCA variants carriers and 0.06% (1/1682) overall. We evaluated the performance of the genetic testing criteria by NCCN and the Brazilian National Health Agency (ANS). The inclusion criteria currently used in Brazil fail to identify 17%-25% of carriers of P/LP variants in hereditary cancer genes. Our results add knowledge on the Brazilian spectrum of cancer risk germline variants, demonstrate that large multigene panels have high positivity rates, and indicate that Brazilian inclusion criteria for genetic testing should be improved.

SUBMITTER: de Oliveira JM

PROVIDER: S-EPMC9259741 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients.

de Oliveira Jarbas Maciel JM Zurro Nuria Bengala NB Coelho Antonio Victor Campos AVC Caraciolo Marcel Pinheiro MP de Alexandre Rodrigo Bertollo RB Cervato Murilo Castro MC Minillo Renata Moldenhauer RM de Vasconcelos Carvalho Neto George G Grivicich Ivana I Oliveira João Bosco JB

European journal of human genetics : EJHG 20220509 7

Hereditary cancer risk syndromes are caused by germline variants, commonly in tumor suppressor genes. Most studies on hereditary cancer have been conducted in white populations. We report the largest study in Brazilian individuals with multiple ethnicities. We genotyped 1682 individuals from all country regions with Next-generation sequencing (NGS) panels. Most were women with a personal/family history of cancer, mostly breast and ovarian. We identified 321 pathogenic/likely pathogenic (P/LP) va ...[more]

PMID: 35534704

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Project description:BackgroundFour Fanconi anemia (FA) genes (BRCA1, BRCA2, PALB2 and RAD51C) are defined as breast cancer (BC) susceptibility genes. Other FA genes have been inconsistently associated with BC. Thus, the role of other FA genes in BC should be explored in specific populations.MethodsMutations in 16 FA genes were screened with a 98-gene panel sequencing assay in a cohort of 1481 Chinese patients with high-risk hereditary BC. The association between mutations and clinicopathological characteristics as well as prognosis was analyzed. The risk of BC in carriers of FA gene mutations was assessed in the Genome Aggregation Database and the Westlake Biobank for Chinese cohort.ResultsA total of 2.57% (38/1481) BC patients were identified who had 12 other FA gene germline mutations. Among them, the most frequently mutated gene was FANCA (8/1481, 0.54%). These 38 patients carried 35 distinct pathogenic/likely pathogenic variants, of which 21 were novel. We found one rare FANCB deleterious variant (c.1327-3dupT) in our cohort. There was a statistically significant difference in lymph node status between FA gene mutation carriers and non-carriers (p = 0.041). We observed a trend that mutation carriers had larger tumor sizes, lower estrogen receptor (ER) and progesterone receptor (PR) positivity rates, and lower 3.5-year invasive disease-free survival (iDFS) and distant recurrence-free survival (DRFS) rates than non-carriers (tumor size > 2 cm: 51.43% vs. 45.63%; ER positivity rates: 51.43% vs. 60.81%; PR positivity rates: 48.57% vs. 55.16%; 3.5-year iDFS rates: 58.8% vs. 66.7%; 3.5-year DRFS rates: 58.8% vs. 68.8%). The frequency of the mutations in FANCD2, FANCM and BRIP1 trended to be higher among BC cases than that in controls (p = 0.055, 0.08 and 0.08, respectively).ConclusionThis study comprehensively estimated the prevalence, clinicopathological characteristics, prognosis and risk of BC associated with deleterious variants in FA genes in Chinese high-risk hereditary BC patients. It enriches our understanding of the role of FA genes with BC.

Project description:Hereditary breast cancer syndromes are associated with an increased risk of breast cancer and constitute a unique patient population, making up approximately 5%-10% of breast cancer cases in the United States. By virtue of the germline mutations that define these syndromes, invasive breast cancers in these patients have unique mechanisms that can be rationally targeted for therapeutic opportunities distinct from standard of care treatments in nongermline mutation associated breast cancers. This review intends to describe existing data on several of the most common hereditary breast cancer syndromes, including BRCA-related breast cancer syndrome, Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer syndrome, specifically focusing on rational therapeutics utilized in these distinct patient subgroups and completed or ongoing clinical trials evaluating their efficacy. By exploiting the distinct biologic features associated with these syndromes, tailored treatment strategies have the potential for improved efficacy and lower toxicity. Knowledge of the emergence of these targeted cancer therapies is critical for appropriate management in these patients, extending beyond treatment to highlight the need for appropriate genetic screening to allow for early recognition of these patients and therefore appropriate treatment.Molecular testing allows for identification of germline mutations that place individuals at high risk for breast cancer and that are associated with distinct histopathology and molecular characteristics that define the invasive breast cancer cases that these patients develop. These unique characteristics may ultimately provide rational targets for systemic treatments with improvements in both morbidity and efficacy. Identification of patients with these germline mutations is important for not only appropriate screening and prophylaxis, but knowledge of therapies specifically targeting several of the most common hereditary breast cancer syndromes is essential to ensure appropriate treatment of invasive breast cancers in these patients.

Dataset Information

The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients.

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The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients.

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