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
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: 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.