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

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.

Automated summary

This study is the largest of its kind in Brazil, focusing on hereditary cancer risk in individuals with multiple ethnicities. Through genotyping 1682 individuals, 321 pathogenic/likely pathogenic variants were identified. The research indicates that current genetic testing criteria in Brazil fail to identify a substantial portion of carriers, highlighting the high positivity rates of large multigene panels and suggesting the need for improved inclusion criteria.