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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 3/2013

01-12-2013 | Translational Research and Biomarkers

Frequent Alterations of MCPH1 and ATM are Associated with Primary Breast Carcinoma: Clinical and Prognostic Implications

Authors: Nilanjana Bhattacharya, PhD, Nupur Mukherjee, MSc, Ratnesh K. Singh, PhD, Satyabrata Sinha, PhD, Neyaz Alam, MS, Anup Roy, MD, Susanta Roychoudhury, PhD, Chinmay Kumar Panda, PhD

Published in: Annals of Surgical Oncology | Special Issue 3/2013

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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.
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Metadata
Title
Frequent Alterations of MCPH1 and ATM are Associated with Primary Breast Carcinoma: Clinical and Prognostic Implications
Authors
Nilanjana Bhattacharya, PhD
Nupur Mukherjee, MSc
Ratnesh K. Singh, PhD
Satyabrata Sinha, PhD
Neyaz Alam, MS
Anup Roy, MD
Susanta Roychoudhury, PhD
Chinmay Kumar Panda, PhD
Publication date
01-12-2013
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue Special Issue 3/2013
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-012-2715-6

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