Diversity index as a novel prognostic factor in breast cancer
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Yul Ri Chung1,2, Hyun Jeong Kim2, Young A. Kim3, Mee Soo Chang1,3, Ki-Tae Hwang4 and So Yeon Park1,2
1Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
2Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Republic of Korea
3Department of Pathology, Seoul National University Boramae Hospital, Seoul, Republic of Korea
4Department of Surgery, Seoul National University Boramae Hospital, Seoul, Republic of Korea
So Yeon Park, email: [email protected]
Keywords: heterogeneity, Shannon index, c-MYC, FGFR1, copy number variation
Received: June 08, 2017 Accepted: August 28, 2017 Published: September 28, 2017
Intratumoral genetic heterogeneity leads to tumor progression and therapeutic resistance. However, due to the difficulty associated with its assessment, the use of this heterogeneity as a prognostic or predictive marker remains limited. To investigate the significance of the Shannon diversity index of gene copy number variation as a tool for measuring genetic heterogeneity in breast cancer, we performed fluorescence in situ hybridization of c-MYC in two sets of invasive breast cancer samples and correlated the Shannon index of c-MYC copy number variation with clinicopathologic features and patient survival. The Shannon index was correlated with average c-MYC copy number and was higher in tumors in which c-MYC was amplified and in those with c-MYC genetic or regional heterogeneity. A high Shannon index was associated with adverse pathologic features including high histologic grade, lymphovascular invasion, p53 overexpression, high Ki-67 proliferation index and negative hormone receptor status. It was also associated with poor disease-free survival in the whole group, in a subgroup excluding c-MYC-amplified cases, and in the hormone receptor-positive subgroup of both a test and a validation set. A high Shannon index for FGFR1 gene copy number variation was also an independent adverse prognostic factor. Our findings suggest that the Shannon diversity index is a measure of intratumoral heterogeneity and can be used as a prognostic factor in breast cancer.
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