title: Frequent alterations of MCPH1 and ATM are associated with primary breast carcinoma: clinical and prognostic implications.
abstract: BACKGROUND
  MCPH1 is a proximal regulator of DNA damage response pathway that is involved in recruitment of phosphorylated ATM to double-stranded DNA breaks.
  
  
  METHODS
  To understand the importance of MCPH1 and ATM in deregulation of DNA damage response pathway in breast carcinoma, we studied m-RNA expression and genetic/epigenetic alterations of these genes in primary breast carcinoma samples.
  
  
  RESULTS
  Our study revealed reduced expression (mRNA/protein) and high alterations (deletion/methylation) (96 %, 121 of 126) of MCPH1 and ATM. Mutation was, however, rare in inactivation of MCPH1. In immunohistochemical analysis, reduced protein expression of MCPH1, ATM and p-ATM were concordant with their molecular alterations (P = 0.03-0.01). Alterations of MCPH1 and deletion of ATM were significantly high in estrogen/progesterone receptor-negative than estrogen/progesterone receptor-positive breast carcinoma samples compared to early or late age of onset tumors, indicating differences in pathogenesis of the molecular subtypes (P = 0.004-0.01). These genes also showed differential association with tumor stage, grade and lymph node status in different subtypes of breast carcinoma (P = 0.00001-0.01). Their coalterations showed significant association with tumor progression and prognosis (P = 0.003-0.05). Interestingly, patients with alterations of these genes or MCPH1 alone had poor outcome after treatment with DNA-interacting drugs and/or radiation (P = 0.01-0.05).
  
  
  CONCLUSIONS
  Inactivation of MCPH1-ATM-associated DNA damage response pathway might have an important role in the development of breast carcinoma with diagnostic, prognostic and therapeutic implications.
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Bhattacharya
authors.forename: Nupur
authors.initials: N
authors.lastname: Mukherjee
authors.forename: Ratnesh K
authors.initials: RK
authors.lastname: Singh
authors.forename: Satyabrata
authors.initials: S
authors.lastname: Sinha
authors.forename: Neyaz
authors.initials: N
authors.lastname: Alam
authors.forename: Anup
authors.initials: A
authors.lastname: Roy
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
authors.forename: Chinmay Kumar
authors.initials: CK
authors.lastname: Panda
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins