title: Characterization of genomic alterations in radiation-associated breast cancer among childhood cancer survivors, using comparative genomic hybridization (CGH) arrays.
abstract: Ionizing radiation is an established risk factor for breast cancer. Epidemiologic studies of radiation-exposed cohorts have been primarily descriptive; molecular events responsible for the development of radiation-associated breast cancer have not been elucidated. In this study, we used array comparative genomic hybridization (array-CGH) to characterize genome-wide copy number changes in breast tumors collected in the Childhood Cancer Survivor Study (CCSS). Array-CGH data were obtained from 32 cases who developed a second primary breast cancer following chest irradiation at early ages for the treatment of their first cancers, mostly Hodgkin lymphoma. The majority of these cases developed breast cancer before age 45 (91%, n = 29), had invasive ductal tumors (81%, n = 26), estrogen receptor (ER)-positive staining (68%, n = 19 out of 28), and high proliferation as indicated by high Ki-67 staining (77%, n = 17 out of 22). Genomic regions with low-copy number gains and losses and high-level amplifications were similar to what has been reported in sporadic breast tumors, however, the frequency of amplifications of the 17q12 region containing human epidermal growth factor receptor 2 (HER2) was much higher among CCSS cases (38%, n = 12). Our findings suggest that second primary breast cancers in CCSS were enriched for an "amplifier" genomic subgroup with highly proliferative breast tumors. Future investigation in a larger irradiated cohort will be needed to confirm our findings.
authors.affiliation: Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Xiaohong R
authors.initials: XR
authors.lastname: Yang
authors.affiliation: Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Killian
authors.affiliation: Department of Laboratory Medicine and Pathology, Children's Hospital and Ohio State University College of Medicine, Columbus, Ohio, United States of America.
authors.forename: Sue
authors.initials: S
authors.lastname: Hammond
authors.affiliation: Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Burke
authors.affiliation: Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Hunter
authors.initials: H
authors.lastname: Bennett
authors.affiliation: Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Davis
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Strong
authors.affiliation: Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Neglia
authors.affiliation: Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Stovall
authors.affiliation: Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Rita E
authors.initials: RE
authors.lastname: Weathers
authors.affiliation: Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Robison
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Smita
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Mabuchi
authors.affiliation: Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Inskip
authors.affiliation: Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
mesh_terms: D000328:Adult; D000069586:Adult Survivors of Child Adverse Events; D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D055028:Comparative Genomic Hybridization / Q000379:methods*; D056915:DNA Copy Number Variations; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008875:Middle Aged; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D055815:Young Adult
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human