The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers
Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs fr...
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| Published in | JNCI : Journal of the National Cancer Institute Vol. 110; no. 9; pp. 1030 - 1034 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Oxford University Press
01.09.2018
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0027-8874 1460-2105 1460-2105 |
| DOI | 10.1093/jnci/djy028 |
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| Abstract | Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic. |
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| AbstractList | Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic. Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic.Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic. |
| Author | Riaz, Nadeem Geyer, Felipe C Jayakumaran, Gowtham Norton, Larry Weigelt, Britta Li, Anqi Couch, Fergus J Selenica, Pier Blecua, Pedro Shen, Ronglai Eccles, Diana M Robson, Mark E Chenevix-Trench, Georgia Powell, Simon N Mandelker, Diana L Kumar, Rahul Lim, Raymond S Blows, Fiona Pareja, Fresia Bi, Rui Waddell, Nic James, Paul A Pharoah, Paul Reis-Filho, Jorge S Wen, Hannah Y |
| AuthorAffiliation | 10 Department of Oncology, University of Cambridge, Cambridge, UK (FB, PP) 7 kConFab Research Department (kI) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia 5 Department of Pathology, Fudan University Cancer Center, Shanghai, China (RB, AL) 1 Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY 4 Department of Medicine (LN, MER) Memorial Sloan Kettering Cancer Center, New York, NY 8 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN (FJC) 9 Southampton Clinical Trials Unit, University of Southampton, Southampton, UK (DME) 6 Familial Cancer Centre (PAJ) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia 3 Epidemiology and Biostatistics (RS) Memorial Sloan Kettering Cancer Center, New York, NY 2 Radiation Oncology (PB, SNP, NR) Memorial Sloan Kettering Cancer Center, New York, NY 11 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia (NW, GCT) |
| AuthorAffiliation_xml | – name: 6 Familial Cancer Centre (PAJ) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia – name: 4 Department of Medicine (LN, MER) Memorial Sloan Kettering Cancer Center, New York, NY – name: 10 Department of Oncology, University of Cambridge, Cambridge, UK (FB, PP) – name: 9 Southampton Clinical Trials Unit, University of Southampton, Southampton, UK (DME) – name: 1 Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY – name: 11 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia (NW, GCT) – name: 8 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN (FJC) – name: 2 Radiation Oncology (PB, SNP, NR) Memorial Sloan Kettering Cancer Center, New York, NY – name: 5 Department of Pathology, Fudan University Cancer Center, Shanghai, China (RB, AL) – name: 7 kConFab Research Department (kI) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia – name: 3 Epidemiology and Biostatistics (RS) Memorial Sloan Kettering Cancer Center, New York, NY |
| Author_xml | – sequence: 1 givenname: Britta surname: Weigelt fullname: Weigelt, Britta organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 2 givenname: Rui surname: Bi fullname: Bi, Rui organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY, Department of Pathology, Fudan University Cancer Center, Shanghai, China (RB, AL) – sequence: 3 givenname: Rahul surname: Kumar fullname: Kumar, Rahul organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 4 givenname: Pedro surname: Blecua fullname: Blecua, Pedro organization: Radiation Oncology (PB, SNP, NR) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 5 givenname: Diana L surname: Mandelker fullname: Mandelker, Diana L organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 6 givenname: Felipe C surname: Geyer fullname: Geyer, Felipe C organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 7 givenname: Fresia surname: Pareja fullname: Pareja, Fresia organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 8 givenname: Paul A surname: James fullname: James, Paul A organization: Familial Cancer Centre (PAJ) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia – sequence: 9 givenname: Fergus J surname: Couch fullname: Couch, Fergus J organization: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN (FJC) – sequence: 10 givenname: Diana M surname: Eccles fullname: Eccles, Diana M organization: Southampton Clinical Trials Unit, University of Southampton, Southampton, UK (DME) – sequence: 11 givenname: Fiona surname: Blows fullname: Blows, Fiona organization: Department of Oncology, University of Cambridge, Cambridge, UK (FB, PP) – sequence: 12 givenname: Paul surname: Pharoah fullname: Pharoah, Paul organization: Department of Oncology, University of Cambridge, Cambridge, UK (FB, PP) – sequence: 13 givenname: Anqi surname: Li fullname: Li, Anqi organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY, Department of Pathology, Fudan University Cancer Center, Shanghai, China (RB, AL) – sequence: 14 givenname: Pier surname: Selenica fullname: Selenica, Pier organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 15 givenname: Raymond S surname: Lim fullname: Lim, Raymond S organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 16 givenname: Gowtham surname: Jayakumaran fullname: Jayakumaran, Gowtham organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 17 givenname: Nic surname: Waddell fullname: Waddell, Nic organization: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia (NW, GCT) – sequence: 18 givenname: Ronglai surname: Shen fullname: Shen, Ronglai organization: Epidemiology and Biostatistics (RS) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 19 givenname: Larry surname: Norton fullname: Norton, Larry organization: Department of Medicine (LN, MER) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 20 givenname: Hannah Y surname: Wen fullname: Wen, Hannah Y organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 21 givenname: Simon N surname: Powell fullname: Powell, Simon N organization: Radiation Oncology (PB, SNP, NR) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 22 givenname: Nadeem surname: Riaz fullname: Riaz, Nadeem organization: Radiation Oncology (PB, SNP, NR) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 23 givenname: Mark E surname: Robson fullname: Robson, Mark E organization: Department of Medicine (LN, MER) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 24 givenname: Jorge S surname: Reis-Filho fullname: Reis-Filho, Jorge S organization: Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY – sequence: 25 givenname: Georgia surname: Chenevix-Trench fullname: Chenevix-Trench, Georgia organization: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia (NW, GCT) |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29506079$$D View this record in MEDLINE/PubMed |
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| Copyright | The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com 2018 |
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| SubjectTerms | Adult Aged Ataxia Telangiectasia Mutated Proteins - genetics Biomarkers, Tumor Breast Neoplasms - diagnosis Breast Neoplasms - genetics Brief Communications Exome Sequencing Female Genetic Association Studies Genetic Predisposition to Disease Genomics - methods Germ-Line Mutation Heterozygote Humans Middle Aged Mutation |
| Title | The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers |
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