Hot Paper in Medicine

May 2014

“Intratumour heterogeneity and branched evolution revealed by multiregion sequencing,” by Marco Gerlinger, et al., New England Journal of Medicine, 366(10): 883-92, 8 March 2012.    

[Authors' affiliations: 7 institutions worldwide


Abstract: “BACKGROUND Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. METHODS To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. RESULTS Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. CONCLUSIONS Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection.”


This 2012 report from the New England Journal of Medicine was cited 55 times in current journal articles indexed by Thomson Reuters during November-December 2013. During that two-month period, no other medicine paper published in the last two years, aside from reviews, collected a higher number of citations. Prior to the most recent bimonthly tally, citations to the paper have accrued as follows, as tracked by Essential Science Indicators Hot Papers:


September-October 2013: 65 citations
July-August 2013: 65
May-June 2013: 72
March-April 2013: 64
January-February 2013: 86
November-December 2012: 57
September-October 2012: 41
July-August 2012: 43
May-June 2012: 23
March-April 2012: 10

Total citations to date: 581


SOURCE: Thomson Reuters Web of Science

The data and citation records included in this report are from Thomson Reuters Web of ScienceTM. Web of ScienceTM is a registered trademark of Thomson Reuters. All rights reserved.