Intra-tumor heterogeneity in breast cancer has limited impact on transcriptomic-based molecular profiling

BMC Cancer

Lena Wedlund¹  Mattias Rantalainen²  Johan Lindberg²  Jan Frisell³  Ikram Ullah⁴  Ran Ma⁴  John Lövrot⁴  Gustav Stålhammar⁴  Jonas Bergh⁴  Johan Hartman⁴  Govindasamy-Muralidharan Karthik⁴  Amjad Alkodsi⁵ 

[1] Department of Clinical Pathology and Cytology, Karolinska University Laboratory;Department of Medical Epidemiology and Biostatistics, Karolinska Institutet;Department of Molecular Medicine and Surgery, Karolinska University Hospital;Department of Oncology and Pathology, Karolinska Institutet, CCK;Genome-Scale Biology Research Program Unit, Faculty of Medicine, University of Helsinki;

关键词: Breast cancer;    Molecular diagnostics;    Molecular subtypes;    Intra-tumor transcriptomic heterogeneity;   

DOI  :  10.1186/s12885-017-3815-2

来源: DOAJ

【 摘 要 】

Abstract Background Transcriptomic profiling of breast tumors provides opportunity for subtyping and molecular-based patient stratification. In diagnostic applications the specimen profiled should be representative of the expression profile of the whole tumor and ideally capture properties of the most aggressive part of the tumor. However, breast cancers commonly exhibit intra-tumor heterogeneity at molecular, genomic and in phenotypic level, which can arise during tumor evolution. Currently it is not established to what extent a random sampling approach may influence molecular breast cancer diagnostics. Methods In this study we applied RNA-sequencing to quantify gene expression in 43 pieces (2-5 pieces per tumor) from 12 breast tumors (Cohort 1). We determined molecular subtype and transcriptomic grade for all tumor pieces and analysed to what extent pieces originating from the same tumors are concordant or discordant with each other. Additionally, we validated our finding in an independent cohort consisting of 19 pieces (2-6 pieces per tumor) from 6 breast tumors (Cohort 2) profiled using microarray technique. Exome sequencing was also performed on this cohort, to investigate the extent of intra-tumor genomic heterogeneity versus the intra-tumor molecular subtype classifications. Results Molecular subtyping was consistent in 11 out of 12 tumors and transcriptomic grade assignments were consistent in 11 out of 12 tumors as well. Molecular subtype predictions revealed consistent subtypes in four out of six patients in this cohort 2. Interestingly, we observed extensive intra-tumor genomic heterogeneity in these tumor pieces but not in their molecular subtype classifications. Conclusions Our results suggest that macroscopic intra-tumoral transcriptomic heterogeneity is limited and unlikely to have an impact on molecular diagnostics for most patients.

【 授权许可】

Unknown