Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2-negative patients with early-onset breast cancer

Prodosmo, Andrea; Buffone, Amelia; Mattioni, Manlio; Barnabei, Agnese; Persichetti, Agnese; Leo, Aurora De; Appetecchia, Marialuisa; Nicolussi, Arianna; Coppa, Anna; Sciacchitano, Salvatore; Giordano, Carolina; Pinnarò, Paola; Sanguineti, Giuseppe; Strigari, Lidia; Alessandrini, Gabriele; Facciolo, Francesco; Cosimelli, Maurizio; Grazi, Gian Luca; Corrado, Giacomo; Vizza, Enrico; Giannini, Giuseppe; Soddu, Silvia

doi:10.1186/s13046-016-0410-3

Cited by 9 publications

(5 citation statements)

References 35 publications

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“…Interestingly, we observed no LOH for ATM variants, in line with the hypothesis that one mutant ATM allele may be sufficient to promote tumor initiation . Importantly, both ATM mutations were also picked up by the p53 mitotic centrosomal localization test, indicating they are functionally impaired in governing p53 centrosomal localization . Overall, our data strongly support the role of these ATM mutations in cancer development, in these families.…”

Section: Discussionsupporting

confidence: 85%

Optimizing the identification of risk‐relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families

et al. 2017

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The introduction of multigene panel testing for hereditary breast/ovarian cancer screening has greatly improved efficiency, speed, and costs. However, its clinical utility is still debated, mostly due to the lack of conclusive evidences on the impact of newly discovered genetic variants on cancer risk and lack of evidence‐based guidelines for the clinical management of their carriers. In this pilot study, we aimed to test whether a systematic and multiparametric characterization of newly discovered mutations could enhance the clinical utility of multigene panel sequencing. Out of a pool of 367 breast/ovarian cancer families Sanger‐sequenced for BRCA1 and BRCA2 gene mutations, we selected a cohort of 20 BRCA1/2‐negative families to be subjected to the BROCA‐Cancer Risk Panel massive parallel sequencing. As a strategy for the systematic characterization of newly discovered genetic variants, we collected blood and cancer tissue samples and established lymphoblastoid cell lines from all available individuals in these families, to perform segregation analysis, loss‐of‐heterozygosity and further molecular studies. We identified loss‐of‐function mutations in 6 out 20 high‐risk families, 5 of which occurred on BRCA1,CHEK2 and ATM and are esteemed to be risk‐relevant. In contrast, a novel RAD50 truncating mutation is most likely unrelated to breast cancer. Our data suggest that integrating multigene panel testing with a pre‐organized, multiparametric characterization of newly discovered genetic variants improves the identification of risk‐relevant alleles impacting on the clinical management of their carriers.

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Section: Discussionsupporting

confidence: 85%

Optimizing the identification of risk‐relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families

et al. 2017

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“…This was first demonstrated in a large group of A-T patients together with their parents, as obligate healthy carriers of pathogenic mutations, compared with wild-type healthy donors [81]. A preliminary study performed on BC patients carrying germline ATM missense variants or small deletions in both exonic and intronic regions showed that p53-MCL was impaired, highlighting its potentiality for the detection of ATM pathogenic mutations also in BC [84]. These data suggest that the p53-MCL test could represent a new functional tool to easily help in the classification of ATM VUS in neoplastic diseases.…”

Section: Atm Variants and A New Possible Functional Assay: The P53 MImentioning

confidence: 96%

Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers

Federici¹,

Soddu²

2020

J Exp Clin Cancer Res

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142

109

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The promising expectations about personalized medicine have opened the path to routine large-scale sequencing and increased the importance of genetic counseling for hereditary cancers, among which hereditary breast and ovary cancers (HBOC) have a major impact. High-throughput sequencing, or Next-Generation Sequencing (NGS), has improved cancer patient management, ameliorating diagnosis and treatment decisions. In addition to its undeniable clinical utility, NGS is also unveiling a large number of variants that we are still not able to clearly define and classify, the variants of uncertain significance (VUS), which account for about 40% of total variants. At present, VUS use in the clinical context is challenging. Medical reports may omit this kind of data and, even when included, they limit the clinical utility of genetic information. This has prompted the scientific community to seek easily applicable tests to accurately classify VUS and increase the amount of usable information from NGS data. In this review, we will focus on NGS and classification systems for VUS investigation, with particular attention on HBOCrelated genes and in vitro functional tests developed for ameliorating and accelerating variant classification in cancer.

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“…This ATM-dependent centrosomal localization of p53 is so consistent during the cell cycle as to allow us to develop a functional test to identify individuals carrying mutations in the ATM gene 29 . In particular, by measuring the percentage of mitotic cells in which p53 colocalizes with the centrosomes in lymphoblastoid cell lines (LCLs) and in cell cycle-reactivated peripheral blood mononuclear cells (PBMCs), we have been able to discriminate healthy individuals (i.e., wild-type ATM alleles; p53-MCL > 75%) from Ataxia-Telangiectasia (A-T) patients (i.e., biallelic ATM mutations; p53-MCL < 30%) and from A-T healthy carriers (i.e., monoallelic ATM mutations; p53-MCL > 40% < 60%) 29,32 . However, which is the function of the ATM-p53 axis at the centrosome is still unclear.…”

Section: Introductionmentioning

confidence: 99%

p53 mitotic centrosome localization preserves centrosome integrity and works as sensor for the mitotic surveillance pathway

et al. 2019

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Centrosomal p53 has been described for three decades but its role is still unclear. We previously reported that, in proliferating human cells, p53 transiently moves to centrosomes at each mitosis. Such p53 mitotic centrosome localization (p53-MCL) occurs independently from DNA damage but requires ATM-mediated p53Ser15 phosphorylation (p53Ser15P) on discrete cytoplasmic p53 foci that, through MT dynamics, move to centrosomes during the mitotic spindle formation. Here, we show that inhibition of p53-MCL, obtained by p53 depletion or selective impairment of p53 centrosomal localization, induces centrosome fragmentation in human nontransformed cells. In contrast, tumor cells or mouse cells tolerate p53 depletion, as expected, and p53-MCL inhibition. Such tumor- and species-specific behavior of centrosomal p53 resembles that of the recently identified sensor of centrosome-loss, whose activation triggers the mitotic surveillance pathway in human nontransformed cells but not in tumor cells or mouse cells. The mitotic surveillance pathway prevents the growth of human cells with increased chance of making mitotic errors and accumulating numeral chromosome defects. Thus, we evaluated whether p53-MCL could work as a centrosome-loss sensor and contribute to the activation of the mitotic surveillance pathway. We provide evidence that centrosome-loss triggered by PLK4 inhibition makes p53 orphan of its mitotic dock and promotes accumulation of discrete p53Ser15P foci. These p53 foci are required for the recruitment of 53BP1, a key effector of the mitotic surveillance pathway. Consistently, cells from patients with constitutive impairment of p53-MCL, such as ATM- and PCNT-mutant carriers, accumulate numeral chromosome defects. These findings indicate that, in nontransformed human cells, centrosomal p53 contributes to safeguard genome integrity by working as sensor for the mitotic surveillance pathway.

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Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2-negative patients with early-onset breast cancer

Cited by 9 publications

References 35 publications

Optimizing the identification of risk‐relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families

Optimizing the identification of risk‐relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families

Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers

p53 mitotic centrosome localization preserves centrosome integrity and works as sensor for the mitotic surveillance pathway

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