title: Rare variants of ATM and risk for Hodgkin's disease and radiation-associated breast cancers.
abstract: OBJECTIVE
  In this study, we first sought to evaluate whether individuals heterozygous for ATM mutations may have an increased susceptibility to radiation-induced breast cancer (BC) after treatment for Hodgkin's disease (HD). We next sought to determine the frequency of ATM variants in patients with Hodgkin's lymphoma, regardless of coexisting BC, compared with healthy volunteers.
  
  
  METHODS
  Full sequence analysis of ATM was performed on cDNA from peripheral blood lymphocytes from 37 cases of BC after therapeutic radiation therapy for HD and 27 comparison cases with HD and no BC treated during the same time period. The frequency of ATM variants was analyzed in the total group of 64 cases of HD and compared to allele frequencies in 128 ethnically matched controls from the same geographical region.
  
  
  RESULTS
  No protein-truncating ATM mutations were observed in cases with HD with or without BC. Missense mutations were more frequent in the cohort with HD compared with patients with BC following HD (P = 0.02). The median time from HD to the development of BC was 18 years in patients with ATM variants compared with 16 years in those with no ATM variants (P = 0.04). Multiple ATM variants, including one homozygous mutation, were observed in 9 HD cases.
  
  
  CONCLUSIONS
  Heterozygous protein-truncating or missense mutations of ATM were not associated with increased radiation-associated risk of BC after HD. The observation of multiple germ-line mutations and a homozygote suggests that rare ATM variants may constitute cancer-susceptibility alleles in a subset of cases.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Shlomit
authors.initials: S
authors.lastname: Gilad
authors.forename: Shoshana
authors.initials: S
authors.lastname: Paglin
authors.forename: Prema
authors.initials: P
authors.lastname: Kolachana
authors.forename: Laila C
authors.initials: LC
authors.lastname: Roisman
authors.forename: Khedoudja
authors.initials: K
authors.lastname: Nafa
authors.forename: Vincent
authors.initials: V
authors.lastname: Yeugelewitz
authors.forename: Maria
authors.initials: M
authors.lastname: Gonzales
authors.forename: Mark
authors.initials: M
authors.lastname: Robson
authors.forename: Deborah
authors.initials: D
authors.lastname: McDermott
authors.forename: Heather Hanson
authors.initials: HH
authors.lastname: Pierce
authors.forename: Noah D
authors.initials: ND
authors.lastname: Kauff
authors.forename: Paz
authors.initials: P
authors.lastname: Einat
authors.forename: Suresh
authors.initials: S
authors.lastname: Jhanwar
authors.forename: Jaya M
authors.initials: JM
authors.lastname: Satagopan
authors.forename: Carole
authors.initials: C
authors.lastname: Oddoux
authors.forename: Nathan
authors.initials: N
authors.lastname: Ellis
authors.forename: Rami
authors.initials: R
authors.lastname: Skaliter
authors.forename: Joachim
authors.initials: J
authors.lastname: Yahalom
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002648:Child; D015331:Cohort Studies; D018076:DNA, Complementary / Q000032:analysis; D004268:DNA-Binding Proteins; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D006689:Hodgkin Disease / Q000532:radiotherapy*; D006801:Humans; D008214:Lymphocytes / Q000097:blood / Q000378:metabolism; D008297:Male; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012334:RNA, Neoplasm / Q000097:blood; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases