Characterization of New ATM Deletion Associated with Hereditary Breast Cancer

Parenti, Sandra; Rabacchi, Claudio; Marino, Marco; Tenedini, Elena; Artuso, Lucia; Castellano, Sara; Carretta, Chiara; Mallia, Selene; Cortesi, Laura; Toss, Angela; Barbieri, Elena; Manfredini, Rossella; Luppi, Mario; Trenti, Tommaso; Tagliafico, Enrico

doi:10.3390/genes12020136

Cited by 7 publications

(13 citation statements)

References 14 publications

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“…This likely pathogenic variant has also previously been reported in individuals with a personal and/or family history of breast and/or ovarian cancer [ 34 , 42 ]. It is noteworthy that one of the ATM mutations described in our population, c.2838+2162_4110-292del, has been recently characterized at a molecular level by our research group [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers

Toss

Tenedini

Piombino

et al. 2021

Genes

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The most common breast cancer (BC) susceptibility genes beyond BRCA1/2 are ATM and CHEK2. For the purpose of exploring the clinicopathologic characteristics of BC developed by ATM or CHEK2 mutation carriers, we reviewed the archive of our Family Cancer Clinic. Since 2018, 1185 multi-gene panel tests have been performed. Nineteen ATM and 17 CHEK2 mutation carriers affected by 46 different BCs were identified. A high rate of bilateral tumors was observed in ATM (26.3%) and CHEK2 mutation carriers (41.2%). While 64.3% of CHEK2 tumors were luminal A-like, 56.2% of ATM tumors were luminal B-like/HER2-negative. Moreover, 21.4% of CHEK2-related invasive tumors showed a lobular histotype. About a quarter of all ATM-related BCs and a third of CHEK2 BCs were in situ carcinomas and more than half of ATM and CHEK2-related BCs were diagnosed at stage I-II. Finally, 63.2% of ATM mutation carriers and 64.7% of CHEK2 mutation carriers presented a positive BC family history. The biological and clinical characteristics of ATM and CHEK2-related tumors may help improve diagnosis, prognostication and targeted therapeutic approaches. Contralateral mastectomy should be considered and discussed with ATM and CHEK2 mutation carriers at the first diagnosis of BC.

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Section: Discussionmentioning

confidence: 99%

Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers

Toss

Tenedini

Piombino

et al. 2021

Genes

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“…The DNA of the proband was processed by the commercial Hereditary Cancer Solution (HCS) kit (SOPHiA GENETICS, Saint-Sulpice, Switzerland) as described previously [ 26 ]. A total of 26 genes were analyzed using the NGS method ( ATM , APC , BARD1 , BRCA1 , BRCA2 , BRIP1 , CDH1 , CHEK2 , EPCAM (large rearrangement only), FAM175A , MLH1 , MRE11A , MSH2 , MSH6 , MUTYH , NBN , PALB2 , PIK3CA , PMS2 , PTEN , RAD50 , RAD51C , RAD51D , STK11 , TP53 , and XRCC2 ).…”

Section: Methodsmentioning

confidence: 99%

Identification and Characterization of an Exonic Duplication in PALB2 in a Man with Synchronous Breast and Prostate Cancer

Bouras

Lafaye

Léoné

et al. 2022

IJMS

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PALB2 (partner and localizer of BRCA2), as indicated by its name, is a BRCA2-interacting protein that plays an important role in homologous recombination (HR) and DNA double-strand break (DSB) repair. While pathogenic variants of PALB2 have been well proven to confer an increased risk of breast cancer, data on its involvement in prostate cancer (PrC) have not been clearly demonstrated. We investigated, using targeted next generation sequencing (NGS), a 59-year-old Caucasian man who developed synchronous breast and prostate cancers. This genetic investigation allowed to identify an intragenic germline heterozygous duplication in PALB2, implicating intronic repetitive sequences spanning exon 11. This variant was confirmed by multiplex ligation probe amplification (MLPA), and genomic breakpoints have been identified and characterized at the nucleotide level (c.3114-811_3202-1756dup) using an approach based on walking PCR, long range PCR, and Sanger sequencing. RT-PCR using mRNA extracted from lymphocytes and followed by Sanger sequencing revealed a tandem duplication r.3114_3201dup; p.(Gly1068Glufs * 14). This duplication results in the synthesis of a truncated, and most-likely, non-functional protein. These findings expand the phenotypic spectrum of PALB2 variants and may improve the yield of genetic diagnoses in this field.

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“…The DNA of patients II-2 and II-4 was processed by the Hereditary Cancer Solution (HCS) kit (SOPHiA GENETICS, Saint-Sulpice, Switzerland) as described previously [12]. A total of 26 genes are analyzed using the NGS method (ATM, APC, BARD1, BRCA1, Total genomic DNA was extracted from blood samples using the automated procedure implemented on the STARlet platform (Hamilton Company, Reno, NV, USA).…”

Section: Ngs Analysismentioning

confidence: 99%

“…The DNA of patients II-2 and II-4 was processed by the Hereditary Cancer Solution (HCS) kit (SOPHiA GENETICS, Saint-Sulpice, Switzerland) as described previously [12]. A total of 26 genes are analyzed using the NGS method (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2).…”

Section: Ngs Analysismentioning

confidence: 99%

Identification and Characterization of New Alu Element Insertion in the BRCA1 Exon 14 Associated with Hereditary Breast and Ovarian Cancer

Bouras

Léoné

Bonadona

et al. 2021

Genes

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Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant cancer predisposition syndrome characterized by an increased risk of breast and ovarian cancers. Germline pathogenic variants in BRCA1 are found in about 7–10% of all familial breast cancers and 10% of ovarian cancers. Alu elements are the most abundant mobile DNA element in the human genome and are known to affect the human genome by different mechanisms leading to human disease. We report here the detection, by next-generation sequencing (NGS) analysis coupled with a suitable bioinformatics pipeline, of an AluYb8 element in exon 14 of the BRCA1 gene in a family with HBOC history first classified as BRCA-negative by Sanger sequencing and first NGS analysis. The c.4475_c.4476insAluYb8 mutation impacts splicing and induces the skipping of exon 14. As a result, the produced mRNA contains a premature stop, leading to the production of a short and likely non-functional protein (pAla1453Glyfs*10). Overall, our study allowed us to identify a novel pathogenic variant in BRCA1 and showed the importance of bioinformatics tool improvement and versioning.

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Characterization of New ATM Deletion Associated with Hereditary Breast Cancer

Cited by 7 publications

References 14 publications

Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers

Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers

Identification and Characterization of an Exonic Duplication in PALB2 in a Man with Synchronous Breast and Prostate Cancer

Identification and Characterization of New Alu Element Insertion in the BRCA1 Exon 14 Associated with Hereditary Breast and Ovarian Cancer

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