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

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

doi:10.1186/s13046-016-0410-3

Abstract

BackgroundVariant ATM heterozygotes have an increased risk of developing cancer, cardiovascular diseases, and diabetes. Costs and time of sequencing and ATM variant complexity make large-scale, general population screenings not cost-effective yet. Recently, we developed a straightforward, rapid, and inexpensive test based on p53 mitotic centrosomal localization (p53-MCL) in peripheral blood mononuclear cells (PBMCs) that diagnoses mutant ATM zygosity and recognizes tumor-associated ATM polymorphisms.MethodsFresh PBMCs from 496 cancer patients were analyzed by p53-MCL: 90 cases with familial BRCA1/2-positive and -negative breast and/or ovarian cancer, 337 with sporadic cancers (ovarian, lung, colon, and post-menopausal breast cancers), and 69 with breast/thyroid cancer. Variants were confirmed by ATM sequencing.ResultsA total of seven individuals with ATM variants were identified, 5/65 (7.7 %) in breast cancer cases of familial breast and/or ovarian cancer and 2/69 (2.9 %) in breast/thyroid cancer. No variant ATM carriers were found among the other cancer cases. Excluding a single case in which both BRCA1 and ATM were mutated, no p53-MCL alterations were observed in BRCA1/2-positive cases.ConclusionsThese data validate p53-MCL as reliable and specific test for germline ATM variants, confirm ATM as breast cancer susceptibility gene, and highlight a possible association with breast/thyroid cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0410-3) contains supplementary material, which is available to authorized users.

Highlights

Variant Ataxia telangiectasia mutated (ATM) heterozygotes have an increased risk of developing cancer, cardiovascular diseases, and diabetes
Biallelic mutations in the ATM gene cause Ataxiatelangiectasia (A-T), a rare autosomal recessive multisystemic disorder characterized by progressive cerebellar ataxia, immune defects, insulin-resistant diabetes, radiosensitivity, and high risk for malignancy [1, 2]
In A-T patients, the large majority of ATM mutations are protein-truncations or splice-junction variants that can be distinguished by the numerous ATM polymorphisms [6, 7]

Summary

Introduction

Variant ATM heterozygotes have an increased risk of developing cancer, cardiovascular diseases, and diabetes. Heterozygous carriers of variants in the ATM gene (from here on, ATM carriers) are usually asymptomatic and largely considered healthy carriers They have been reported to be more sensitive to ionizing radiation and susceptible to ischemic heart disease, diabetes, and cancer, of the breast, and digestive tract and lung [2, 8]. Along with A-T associated mutations, several ATM screenings in cancer patients identified missense ATM variants, amino acid substitutions that are not expected to be associated with A-T [12]. Discrimination of these ATM variants from ATM polymorphisms and their contribution to health risks is still controversial. Distinguishing between deleterious and neutral ATM alterations is required to allow the definition of standard-of-care clinical guidelines for the management of ATM carriers and their families [11]

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