The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients View Full Text


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Article Info

DATE

2022-05-09

AUTHORS

Jarbas Maciel de Oliveira, Nuria Bengala Zurro, Antonio Victor Campos Coelho, Marcel Pinheiro Caraciolo, Rodrigo Bertollo de Alexandre, Murilo Castro Cervato, Renata Moldenhauer Minillo, George de Vasconcelos Carvalho Neto, Ivana Grivicich, João Bosco Oliveira

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. More... »

PAGES

1-6

References to SciGraph publications

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  • 2018-03-15. The ACMG/AMP reputable source criteria for the interpretation of sequence variants in GENETICS IN MEDICINE
  • 2010-04-07. Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics in BREAST CANCER RESEARCH AND TREATMENT
  • 2015-03-05. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology in GENETICS IN MEDICINE
  • 2017-06-21. Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers in BMC CANCER
  • 2016-11-11. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women in BREAST CANCER RESEARCH
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  • 2004-09-21. The BOADICEA model of genetic susceptibility to breast and ovarian cancer in BRITISH JOURNAL OF CANCER
  • 2012-08-11. Multiple jejunal cancers resulting from combination of germline APC and MLH1 mutations in FAMILIAL CANCER
  • 2014-05-07. Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations in BREAST CANCER RESEARCH AND TREATMENT
  • 2011-08-17. Characteristics of double heterozygosity for BRCA1 and BRCA2 germline mutations in Korean breast cancer patients in BREAST CANCER RESEARCH AND TREATMENT
  • 2004-08-23. Highly penetrant hereditary cancer syndromes in ONCOGENE
  • 2018-06-15. The germline mutational landscape of BRCA1 and BRCA2 in Brazil in SCIENTIFIC REPORTS
  • 2020-08-29. Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis in BREAST CANCER
  • 2018-07-11. Underdiagnosis of Hereditary Breast and Ovarian Cancer in Medicare Patients: Genetic Testing Criteria Miss the Mark in ANNALS OF SURGICAL ONCOLOGY
  • 2015-12-17. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing in GENETICS IN MEDICINE
  • Identifiers

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    http://scigraph.springernature.com/pub.10.1038/s41431-022-01098-7

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    23 schema:description 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.
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    28 schema:keywords BRCA1
    29 BRCA2
    30 Brazil
    31 Brazilian individuals
    32 LP variants
    33 Lynch syndrome genes
    34 MUTYH
    35 NCCN
    36 Overall
    37 PALB2
    38 TP53
    39 agencies
    40 analysis
    41 breast
    42 cancer
    43 cancer genes
    44 carriers
    45 comprehensive analysis
    46 country regions
    47 criteria
    48 ethnicity
    49 family history
    50 genes
    51 genetic testing
    52 genetic testing criteria
    53 genetics
    54 germline variants
    55 health agencies
    56 hereditary cancer
    57 hereditary cancer genes
    58 heterozygosity rate
    59 higher positivity rate
    60 history
    61 inclusion criteria
    62 individuals
    63 knowledge
    64 larger study
    65 most studies
    66 multigene panels
    67 multiple ethnicities
    68 national health agencies
    69 next-generation sequencing panel
    70 ovarian
    71 panel
    72 pathogenic variants
    73 patients
    74 people
    75 performance
    76 personal/family history
    77 population
    78 positivity rate
    79 prevalence
    80 rate
    81 region
    82 results
    83 risk syndrome
    84 samples
    85 sequencing panel
    86 spectra
    87 study
    88 suppressor gene
    89 syndrome
    90 syndrome gene
    91 testing
    92 testing criteria
    93 tumor suppressor gene
    94 variant carriers
    95 variants
    96 white population
    97 women
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