Frequent alterations of MCPH1 and ATM are associated with primary breast carcinoma: clinical and prognostic implications

Bhattacharya, Nilanjana ; Mukherjee, Nupur ; Singh, Ratnesh K. ; Sinha, Satyabrata ; Alam, Neyaz ; Roy, Anup ; Roychoudhury, Susanta ; Panda, Chinmay Kumar (2013) Frequent alterations of MCPH1 and ATM are associated with primary breast carcinoma: clinical and prognostic implications Annals of Surgical Oncology, 20 (S3). pp. 424-432. ISSN 1068-9265

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Official URL: https://link.springer.com/article/10.1245/s10434-0...

Related URL: http://dx.doi.org/10.1245/s10434-012-2715-6

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.

Item Type:Article
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ID Code:105981
Deposited On:21 Dec 2017 11:37
Last Modified:21 Dec 2017 11:37

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