Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings

Bonache, Sandra; Esteban, I.; Moles‐Fernández, Alejandro; Tenés, Anna; Duran-Lozano, Laura; Montalban, Gemma; Bach, Vanessa; Carrasco, Estela; Gadea, Neus; López‐Fernández, Adrià; Torres-Esquius, Sara; Mancuso, Francesco; Caratù, Ginevra; Vivancos, Ana; Tuset, N; Balmañà, Judith; Gutiérrez‐Enríquez, Sara; Dı́ez, Orland

doi:10.1007/s00432-018-2763-9

Cited by 56 publications

(42 citation statements)

References 48 publications

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“…We identified the well‐known colorectal cancer‐associated APC c.3920T>A (p.Ile1307Lys) variant in two unrelated MBC cases with no personal and family history of FAP syndrome. This variant has been reported as a candidate low penetrance BC risk gene or genetic modifier in BRCA1/2 cases . Further studies are needed to elucidate if the APC p.Ile1307Lys variant can play a role as low penetrance allele in MBC susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy

Rizzolo

Zelli

Silvestri

et al. 2019

Intl Journal of Cancer

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Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well‐characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non‐BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer‐associated genes. The main clinical‐pathologic characteristics of MBC in pathogenic variant carriers and non‐carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non‐BRCA1/2 MBC patients were examined in our study. Twenty‐seven of the non‐BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non‐BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.

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Section: Discussionmentioning

confidence: 99%

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy

Rizzolo

Zelli

Silvestri

et al. 2019

Intl Journal of Cancer

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“…Despite truncating variants in those genes being the cause of Lynch Syndrome (LS), it is common to find an overlap between HBOC and LS cases since both syndromes are well known for predisposition to BC and OC [69]. Many studies have reported MMR genes as being associated with an increased risk to HBOC [70][71][72] and indeed, they have been taken into account by NCCN guidelines for the clinical management of patients at risk of hereditary BC and OC [4,73].…”

Section: Discussionmentioning

confidence: 99%

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

et al. 2020

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Background: The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ ovarian cancer, presenting an autosomal dominant inheritance pattern. BRCA1 and BRCA2 are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. However, only 20-30% of HBOC cases present pathogenic variants in those genes, and other DNA repair genes have emerged as increasing the risk for HBOC. In Brazil, variants in ATM, ATR, CHEK2, MLH1, MSH2, MSH6, POLQ, PTEN, and TP53 genes have been reported in up to 7.35% of the studied cases. Here we screened and characterized variants in 21 DNA repair genes in HBOC patients. Methods:We systematically analyzed 708 amplicons encompassing the coding and flanking regions of 21 genes related to DNA repair pathways (ABRAXAS1, ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51, TP53 and UIMC1). A total of 95 individuals with HBOC syndrome clinical suspicion in Southeast Brazil were sequenced, and 25 samples were evaluated for insertions/deletions in BRCA1/BRCA2 genes. Identified variants were assessed in terms of population allele frequency and their functional effects were predicted through in silico algorithms. Results: We identified 80 variants in 19 genes. About 23.4% of the patients presented pathogenic variants in BRCA1, BRCA2 and TP53, a frequency higher than that identified among previous studies in Brazil. We identified a novel variant in ATR, which was predicted as pathogenic by in silico tools. The association analysis revealed 13 missense variants in ABRAXAS1, BARD1, BRCA2, CHEK2, CDH1, MLH1, PALB2, and PMS2 genes, as significantly associated with increased risk to HBOC, and the patients carrying those variants did not present large insertions or deletions in BRCA1/BRCA2 genes.

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“…Additionally, the analysis by targeted sequencing of other BC/OC susceptibility genes in BRCA1 c.4185+4105C>T carrier, including ATM, BRIP1, CHEK2, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11 and TP53 , did not identify any deleterious variant that could explain the family phenotype,19 supporting also a pathogenic role for the BRCA1 deep intronic variant.…”

Section: Discussionmentioning

confidence: 94%

Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer

Montalban¹,

Bonache²,

Moles‐Fernández³

et al. 2018

J Med Genet

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BackgroundGenetic analysis of BRCA1 and BRCA2 for the diagnosis of hereditary breast and ovarian cancer (HBOC) is commonly restricted to coding regions and exon-intron boundaries. Although germline pathogenic variants in these regions explain about ~20% of HBOC cases, there is still an important fraction that remains undiagnosed. We have screened BRCA1/2 deep intronic regions to identify potential spliceogenic variants that could explain part of the missing HBOC susceptibility.MethodsWe analysed BRCA1/2 deep intronic regions by targeted gene sequencing in 192 high-risk HBOC families testing negative for BRCA1/2 during conventional analysis. Rare variants (MAF <0.005) predicted to create/activate splice sites were selected for further characterisation in patient RNA. The splicing outcome was analysed by RT-PCR and Sanger sequencing, and allelic imbalance was also determined when heterozygous exonic loci were present.ResultsA novel transcript was detected in BRCA1 c.4185+4105C>T variant carrier. This variant promotes the inclusion of a pseudoexon in mature mRNA, generating an aberrant transcript predicted to encode for a non-functional protein. Quantitative and allele-specific assays determined haploinsufficiency in the variant carrier, supporting a pathogenic effect for this variant. Genotyping of 1030 HBOC cases and 327 controls did not identify additional carriers in Spanish population.ConclusionScreening of BRCA1/2 intronic regions has identified the first BRCA1 deep intronic variant associated with HBOC by pseudoexon activation. Although the frequency of deleterious variants in these regions appears to be low, our study highlights the importance of studying non-coding regions and performing comprehensive RNA assays to complement genetic diagnosis.

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Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings

Cited by 56 publications

References 48 publications

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer

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