Abstract
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.
Highlights
Intratumoral heterogeneity (ITH), referring to phenotypic differences between cancer cells within the same tumor, has become a major focus of research with advances in molecular technologies
We evaluated the relationship between c-MYC copy number variation and clinicopathologic features (Table 1). c-MYC amplification was associated with high histologic grade, p53 overexpression, high Ki-67 proliferation index, and negative hormone receptor status. c-MYC copy number gain was associated with all of the clinicopathologic features associated with c-MYC amplification in addition to HER2 amplification
Fibroblast growth factor receptor 1 (FGFR1) amplification is a well-known adverse prognostic factor in breast cancer, especially in hormone receptor-positive cases [25,26,27], and we found that FGFR1 amplification was correlated with decreased diseasefree survival in the whole group and in the hormone receptor-positive subgroup, but not in the hormone receptor-negative subgroup (p=0.003, p=0.009, p=0.143, respectively)
Summary
Intratumoral heterogeneity (ITH), referring to phenotypic differences between cancer cells within the same tumor, has become a major focus of research with advances in molecular technologies. It affects important behavioral features including metastatic potential, angiogenesis, migration, evasion of antitumor immunity, and activation of metabolic pathways [1, 2]. This intratumoral diversity leads to therapeutic resistance and presents a major obstacle to cure [3]. We investigated the correlation between the Shannon index for gene copy number variation and clinicopathologic features of breast cancer, and evaluated its prognostic value in breast cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
