title: Genetic and epigenetic analysis of CHEK2 in sporadic breast, colon, and ovarian cancers.
abstract: OBJECTIVE
  Germ-line variants in CHEK2 have been associated with increased breast, thyroid, prostate, kidney, and colorectal cancer risk; however, the prevalence of somatic inactivation of CHEK2 in common cancer types is less clear. The aim of this study was to determine if somatic mutation and/or epigenetic modification play a role in development of sporadic breast, colon, or ovarian cancers.
  
  
  METHODS
  We undertook combined genetic and epigenetic analysis of CHEK2 in sporadic primary breast, ovarian, and colon tumors [all exhibiting chromosome 22q loss of heterozygosity (LOH)] and cancer cell lines. Expression of Chk2 was assessed by immunohistochemistry in 119 ovarian tumors.
  
  
  RESULTS
  Two novel germ-line variants were identified; however, none of the primary tumors harbored somatic mutations. Two CpG clusters previously implicated in CHEK2 silencing were investigated for evidence of hypermethylation. No methylation was detected at the distal CpG island. The proximal CpG cluster was methylated in all tumor and normal DNA, suggesting that this might not represent a true CpG island and is not relevant in the control of CHEK2 expression. Twenty-three percent of ovarian tumors were negative for Chk2 protein by immunohistochemistry, but there was no significant correlation between LOH across the CHEK2 locus and intensity of Chk2 staining (P = 0.12).
  
  
  CONCLUSIONS
  LOH across the CHEK2 locus is common in sporadic breast, ovarian, and colorectal cancers, but point mutation or epigenetic inactivation of the retained allele is uncommon. Loss of Chk2 protein in ovarian cancer was not associated with allelic status, suggesting that inactivation does not occur as a consequence of haploinsufficiency.
authors.affiliation: Victorian Breast Cancer Research Consortium Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Louise H
authors.initials: LH
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Choong
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Johnson
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
mesh_terms: D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D064447:Checkpoint Kinase 2; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004252:DNA Mutational Analysis / Q000379:methods; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D014644:Genetic Variation / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases