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

Grasel, Rebeca Silveira; Felicio, Paula Silva; Paula, André Escremim de; Campacci, Natália; Garcia, Felipe Antonio de Oliveira; Andrade, Edilene Santos de; Evangelista, Adriane Feijó; Fernandes, Gabriela; Sabato, Cristina da Silva; Marchi, Pedro De; Souza, Cristiano de Pádua; Paula, Cláudia Alessandra Andrade de; Torrezan, Giovana Tardin; Galvão, Henrique de Campos Reis; Palmero, Edenir Inêz

doi:10.3389/fonc.2020.571330

Cited by 8 publications

(5 citation statements)

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“…Analysis of the presence of germline variants in BRCA1 / BRCA2 / TP53 genes was conducted at the Center of Molecular Diagnosis of BCH as part of routine care through Sanger/panel NGS sequencing followed by MLPA (Multiplex Ligation‐dependent Probe Amplification Analysis) rearrangement analysis, as previously described (Fernandes et al, 2016). It is worth noting that 36 women, among the 52 included in this study, were previously analyzed in a 14‐gene NGS panel including high and moderate breast/ovarian cancer genes ( ATM, BARD1, BRIP1, CDH1, CHEK2 MRE11, MUTYH, NBN, PALB2, PTEN, RAD50, RAD51C, TP53 , and STK11 ; Grasel et al, 2020 accepted).…”

Section: Methodsmentioning

confidence: 99%

Whole‐exome sequencing of non‐ BRCA1/BRCA2 mutation carrier cases at high‐risk for hereditary breast/ovarian cancer

et al. 2020

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The current study aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole‐exome sequencing (WES) was performed in the germline DNA of 52 non‐BRCA1/BRCA2/TP53 mutation carrier women at high‐risk for hereditary breast and ovarian cancer (HBOC). All variants were classified using information from population and disease specific databases, in silico prediction tools and the American College of Medical Genetics and Genomics (ACMG) criteria. Loss of heterozygosity (LOH) of tumor samples and segregation analyses were performed whenever possible. The variants identified were investigated in a second, independent cohort of 17 BC cases. Pathogenic/Likely Pathogenic variants were identified in known cancer genes such as CHEK2, MUTYH, PMS2, and RAD51C. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, and RAD54L) and other cancer‐related genes such as DROSHA and SLC34A2. Interestingly, the variant c.149T>G in the FAN1 gene was identified in two unrelated families, and exhibited LOH in the tumor tissue of one of them. In conclusion, this is the largest Brazilian WES study involving families at high‐risk for HBOC which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer.

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Section: Methodsmentioning

confidence: 99%

Whole‐exome sequencing of non‐ BRCA1/BRCA2 mutation carrier cases at high‐risk for hereditary breast/ovarian cancer

et al. 2020

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“…The allele frequency of the variants was visually verified with IGV software, 22 and loss of wild-type allele was considered positive when variant allelic fractions were higher than 65% or 15% higher than the VAF in germline DNA. 23 24 This method was previously validated by our group and detected LOH in 90% of breast cancer tissues from BRCA1 GPV carriers (data not shown).…”

Section: Methodsmentioning

confidence: 92%

Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes

et al. 2023

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BackgroundSarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases.MethodsGermline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants.ResultsGPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (TP53,RB1,NF1,EXT1/2) but also in genes where that risk is still emerging/limited (ERCC2,TSC2andBRCA2) or unknown (PALB2,RAD50,FANCMand others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%×6.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk.ConclusionOur findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.

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“…Although a greater number of studies in this review have focused their attention on the CHEK2 and ATM gene, the second most mutated non- BRCA gene, curiously, was MUTYH . Ten different pathogenic variants were found in the MUTYH gene with a total of 34 mutated patients (Additional file 1 ), distributed in three studies [ 24 , 38 , 44 ]. In highlight, the c.1187G > A variant was reported in fifteen patients with HBOC in Brazil, including 13 patients from the cohort of Guindalini et al [ 44 ], been this variant responsible for a significant proportion of pathogenic mutations in the MUTYH gene.…”

Section: Discussionmentioning

confidence: 99%

Systematic review of the molecular basis of hereditary breast and ovarian cancer syndrome in Brazil: the current scenario

de Freitas Ribeiro,

Junior,

dos Santos

2024

Eur J Med Res

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Background A detailed understanding of the genetic basis of cancer is of great interest to public health monitoring programs. Although many studies have been conducted in Brazil, a global view on the molecular profile related to hereditary breast and ovarian cancer (HBOC) in this large and heterogeneous population is lacking. Methods A systematic review following the PRISMA guidelines was conducted in three electronic databases (PubMed, BIREME and SciELO). Brazilian studies covering molecular analysis of genes related to HBOC, published until December 2023, were considered. Results We identified 35 original studies that met all the inclusion criteria. A total of 137 distinct mutations were found in the BRCA1 gene, but four of them corresponded to 44.5% of all mutations found in this gene. The c.5266dupC BRCA1 mutation was responsible for 26.8% of all pathogenic mutations found in the BRCA1 gene in patients with clinical criteria for HBOC from the Brazilian population. Considering all studies that track this mutation in the BRCA1 gene, we found a frequency of 2% (120/6008) for this mutation in Brazilian patients. In the BRCA2 gene, the four most frequent mutations corresponded to 29.2% of pathogenic mutations. Even though it was tracked by few studies, the c.156_157insAlu mutation was responsible for 9.6% of all pathogenic mutations reported in the BRCA2 gene. Seventeen studies found pathogenic mutations in other non-BRCA genes, the c.1010G > A mutation in the TP53 gene being the most frequent one. Considering all studies that screened for this specific mutation in patients with the clinical criteria for HBOC, the frequency of c.1010G > A was estimated at 1.83% (61/3336). Conclusions Despite significant molecular heterogeneity among mutations in HBOC patients from Brazil, three mutations deserve to be highlighted, c.5266dupC, c.156_157insAlu and c.1010G > A in the BRCA1, BRCA2 and TP53 genes, respectively. With more than 200 records, these three mutations play a vital role in the pathology of breast and ovarian cancer in Brazil. The data collected shed light on the subject, but there is still not enough data from certain subpopulations.

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

Cited by 8 publications

References 37 publications

Whole‐exome sequencing of non‐ BRCA1/BRCA2 mutation carrier cases at high‐risk for hereditary breast/ovarian cancer

Whole‐exome sequencing of non‐ BRCA1/BRCA2 mutation carrier cases at high‐risk for hereditary breast/ovarian cancer

Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes

Systematic review of the molecular basis of hereditary breast and ovarian cancer syndrome in Brazil: the current scenario

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