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



Fresh 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.



A 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.



These 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.
Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute - IRCCS, Via Elio Chianesi 53, 00144, Rome, Italy.
Andrea
A
Prodosmo
Department of Molecular Medicine, University La Sapienza, Rome, Italy.
Amelia
A
Buffone
Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute - IRCCS, Via Elio Chianesi 53, 00144, Rome, Italy.
Manlio
M
Mattioni
Endocrinology Unit, Department of Clinical and Experimental Oncology, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Agnese
A
Barnabei
Endocrinology Unit, Department of Clinical and Experimental Oncology, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.|Department of Molecular Medicine, University La Sapienza, Rome, Italy.
Agnese
A
Persichetti
Endocrinology Unit, Department of Clinical and Experimental Oncology, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Aurora
A
De Leo
Endocrinology Unit, Department of Clinical and Experimental Oncology, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Marialuisa
M
Appetecchia
Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I, Viale Regina Elena, 32400161, Rome, Italy.
Arianna
A
Nicolussi
Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I, Viale Regina Elena, 32400161, Rome, Italy.
Anna
A
Coppa
Department of Clinical and Molecular Medicine, University La Sapienza, Laboratorio di Ricerca Biomedica, Fondazione Università Niccolò Cusano per la Ricerca Medico Scientifica, Rome, Italy.
Salvatore
S
Sciacchitano
Radiotherapy Unit, Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Carolina
C
Giordano
Radiotherapy Unit, Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Paola
P
Pinnarò
Radiotherapy Unit, Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Giuseppe
G
Sanguineti
Medical Physics Unit, Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Lidia
L
Strigari
Toracic Surgery Unit, Department of Clinical and Experimental Oncology, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Gabriele
G
Alessandrini
Toracic Surgery Unit, Department of Clinical and Experimental Oncology, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Francesco
F
Facciolo
Hepato-pancreato-biliary Surgery Unit, Department of Clinical and Experimental Oncology, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Maurizio
M
Cosimelli
Hepato-pancreato-biliary Surgery Unit, Department of Clinical and Experimental Oncology, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Gian Luca
GL
Grazi
Gynecological Oncology Unit, Department of Clinical and Experimental Oncology, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Giacomo
G
Corrado
Gynecological Oncology Unit, Department of Clinical and Experimental Oncology, Regina Elena National Cancer Institute - IRCCS, Rome, Italy.
Enrico
E
Vizza
Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Molecular Medicine, University La Sapienza, Rome, Italy. giuseppe.giannini@uniroma1.it.|Department of Molecular Medicine, University La Sapienza, Rome, Italy. giuseppe.giannini@uniroma1.it.
Giuseppe
G
Giannini
Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute - IRCCS, Via Elio Chianesi 53, 00144, Rome, Italy. silvia.soddu@ifo.gov.it.
Silvia
S
Soddu
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D018385:Centrosome / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D008938:Mitosis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
ATM cancer susceptibility gene; BRCA1/2; Early-onset breast cancer; p53-mitotic centrosomal localization (p53-MCL)