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

Felicio, Paula Silva; Grasel, Rebeca Silveira; Campacci, Natália; Paula, André Escremim de; Galvão, Henrique C R; Torrezan, Giovana Tardin; Sabato, Cristina S; Fernandes, Gabriela; Souza, Cleonilson Protásio de; Michelli, Rodrigo D.; Andrade, Carlos; Barros, Bruna Durães de Figueiredo; Matsushita, Marcus; Revil, Timothée; Ragoussis, Jiannis; Couch, Fergus J.; Hart, Steven N.; Reis, Rui Manuel; Melendez, Matias Eliseo; Tonin, Patricia N.; Carraro, Dirce Maria; Palmero, Edenir Inêz

doi:10.1002/humu.24158

Cited by 33 publications

(14 citation statements)

References 38 publications

(40 reference statements)

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“…Among the 56 variants we detected, [35][36][37][38]40 . We also observed some recurrent pathogenic variants in other genes: TP53:c.1010G>A, found in four other studies 20,[38][39][40] , CHEK2:c.349A>G, found in two other studies 38,43 ; MUTYH:c.1147delC 43 Transheterozygosity, i.e. heterozygosity at two different loci 47 , is rare among patients at risk of hereditary cancers.…”

Section: Discussionsupporting

confidence: 71%

“…The five most recurrent variants were: BRCA1:c.5266dupC, found by other 18 studies 18, 20, 24-39 , BRCA1:c.3331_3334delCAAG, found in other 12 studies 18,20,24,27,29,31,32,34,35,37,39,40 , BRCA2:c.2808_2811delACAA found in other seven studies 18, 29-31, 34, 35, 39 , BRCA1: c.1687C>T found in six studies 26,31,32,34,35 and BRCA1:c.211A>G found in other five studies [35][36][37][38]40 . We also observed some recurrent pathogenic variants in other genes: TP53:c.1010G>A, found in four other studies 20,[38][39][40] , CHEK2:c.349A>G, found in two other studies 38,43 ; MUTYH:c.1147delC 43 Transheterozygosity, i.e. heterozygosity at two different loci 47 , is rare among patients at risk of hereditary cancers.…”

Section: Discussionsupporting

confidence: 71%

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

Coelho

et al. 2021

Preprint

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Hereditary cancer risk syndromes are a group of disorders caused by germline variants in a growing number of genes. Most studies on hereditary cancer have been conducted in white populations. Here we report the largest study in Brazilian individuals with multiple, self-reported, ethnicities. We genotyped 1682 individuals from all regions of the country who were referred to genetic testing for hereditary cancer risk with multigene Next-generation sequencing (NGS) panels. Most were women, and had a personal and/or family history of cancer. The majority of cancer cases were breast and ovarian. We identified a total of 321 pathogenic/likely pathogenic (P/LP) variants in 305 people (18.1%), corresponding to 166 unique variants. These variants were distributed among 32 genes, and most were detected on BRCA1 and BRCA2 (129 patients, 26.2% and 14.3% of all P/LP hits, respectively). The prevalence of any genes transheterozygosity in our sample was 0.89% (15/1682). The BRCA1/BRCA2 double heterozygosity rate was 0.78% (1/129) for BRCA variants carriers and 0.06% (1/1682) overall. We classified patients according to the NCCN and Brazilian National Health Agency (ANS) genetic testing recommendation criteria. We found that the criteria had false negative rates of 17.3% and 44.2%, meaning that both failed to detect a substantial part of P/LP positive patients. Therefore, our results show that NGS adds to knowledge on the Brazilian spectrum of germline variants associated with cancer risk and indicate that Brazilian testing guidelines should be improved.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionsupporting

confidence: 71%

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

Coelho

et al. 2021

Preprint

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show abstract

“…A POLQ germline variant of unknown significance, as in the presented family, has already been reported in non- BRCA1/BRCA2 -mutated breast cancer families [ 46 , 47 ]. Other case–control studies also associated missense POLQ variants with an increased risk of breast cancer [ 48 , 49 ]. The presented data, however, suggest that low-frequency POLQ variants might also be involved in hereditary PDAC.…”

Section: Discussionmentioning

confidence: 99%

Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer

Slater

Wilke

Böhm

et al. 2021

JPM

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Familial pancreatic cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 could be detected in 10–15% of analyzed families. Thus, the genetic basis of disease susceptibility in the majority of FPC families remains unknown. In an attempt to identify new candidate genes, we performed whole-genome sequencing on affected patients from 15 FPC families, without detecting BRCA1/2, CDKN2A or PALB2 mutations, using an Illumina based platform. Annotations from CADD, PolyPhen-2, SIFT, Mutation Taster and PROVEAN were used to assess the potential impact of a variant on the function of a gene. Variants that did not segregate with pancreatic disease in respective families were excluded. Potential predisposing candidate genes ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 were identified in 7 of 15 families. All identified gene mutations segregated with pancreatic disease, but sometimes with incomplete penetrance. An analysis of up to 46 additional FPC families revealed that the identified gene mutations appeared to be unique in most cases, despite a potentially deleterious ACAD9 Ala326Thr germline variant, which occurred in 4 (8.7%) of 46 FPC families. Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants.

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“…Interestingly, FAN1 may acquire a key role in cancer cells lacking BRCA2 [34]. BRCA2 is an important factor of HRR and acts as reservoir of the RAD51 recombinase [64,[110][111][112][113]. Deposition of RAD51 by BRCA2 not only facilitates HRR but has a fork-protective function by preventing replication stress in a manner distinct from HRR [114].…”

Section: Cancermentioning

confidence: 99%

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

Deshmukh

Porro

Mohiuddin

et al. 2021

JHD

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FAN1 encodes a DNA repair nuclease. Genetic deficiencies, copy number variants, and single nucleotide variants of FAN1 have been linked to karyomegalic interstitial nephritis, 15q13.3 microdeletion/microduplication syndrome (autism, schizophrenia, and epilepsy), cancer, and most recently repeat expansion diseases. For seven CAG repeat expansion diseases (Huntington’s disease (HD) and certain spinocerebellar ataxias), modification of age of onset is linked to variants of specific DNA repair proteins. FAN1 variants are the strongest modifiers. Non-coding disease-delaying FAN1 variants and coding disease-hastening variants (p.R507H and p.R377W) are known, where the former may lead to increased FAN1 levels and the latter have unknown effects upon FAN1 functions. Current thoughts are that ongoing repeat expansions in disease-vulnerable tissues, as individuals age, promote disease onset. Fan1 is required to suppress against high levels of ongoing somatic CAG and CGG repeat expansions in tissues of HD and FMR1 transgenic mice respectively, in addition to participating in DNA interstrand crosslink repair. FAN1 is also a modifier of autism, schizophrenia, and epilepsy. Coupled with the association of these diseases with repeat expansions, this suggests a common mechanism, by which FAN1 modifies repeat diseases. Yet how any of the FAN1 variants modify disease is unknown. Here, we review FAN1 variants, associated clinical effects, protein structure, and the enzyme’s attributed functional roles. We highlight how variants may alter its activities in DNA damage response and/or repeat instability. A thorough awareness of the FAN1 gene and FAN1 protein functions will reveal if and how it may be targeted for clinical benefit.

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

Cited by 33 publications

References 38 publications

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

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

Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer

FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders

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