CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; John A. Thorson, MD, PhD, associate professor of pathology, director of the Clinical Genomics Laboratory, Center for Advanced Laboratory Medicine, UCSD; Sarah S. Murray, PhD, professor, Department of Pathology, and director of genomic technologies, Center for Advanced Laboratory Medicine, UCSD; and James Solomon, MD, PhD, resident, Department of Pathology, UCSD.
Inter- and intra-genomic heterogeneity in localized, multifocal prostate cancer
Genomic heterogeneity in cancer is not a novel finding; however, comprehensive studies to evaluate intra- and inter-genomic heterogeneity in prostate cancer are lacking. The authors conducted such a study, in which they investigated localized, multifocal disease that is potentially curable but treated as non-indolent cancer. They studied 74 patients in whom they first analyzed index tumors with Gleason score 7 pathology for copy number aberrations (CNAs) using a single nucleotide polymorphism microarray platform. The results of that analysis demonstrated overall heterogeneous profiles with variable percentages of genome alteration across the samples. Inter- and intra-genomic heterogeneity were then assessed by investigating single nucleotide variants, CNAs, and genomic rearrangements in a subset of five of the patients using whole-genome sequencing in 23 distinct tumor regions (two to nine distinct foci from each patient). For each patient, one frozen specimen and one to eight formalin-fixed, paraffin-embedded (FFPE) specimens were sequenced. From this analysis, the authors identified several abnormalities previously associated with prostate cancer, including loss of 8p containing NKX3-1, MYC amplification, loss of 17p13.1 containing TP53, and EGFR amplification. They also identified a novel gene amplification at 1p34.2 encompassing MYCL that almost always occurred with TP53 loss. Fluorescence in situ hybridization analysis of polymerase chain reaction–validated MYCL amplifications provided evidence of focal amplification in a subset of localized prostate cancer. When looking at overall structural variation, extensive inter-tumor diversity was noted, as were large observed differences between regions from the same prostate (intra-tumor diversity). The authors observed a marked reduction in the number of genomic rearrangements in the FFPE-derived specimens compared with the frozen specimens, which they attributed to smaller insert sizes for the FFPE-derived libraries. The authors also found intra-focal heterogeneity of structural variation. In one example they provided, the gene NKX3-1 was deleted in two of the five regions sampled from a single patient’s tumor, providing different predictions of patient prognosis depending on which focus was sampled. When looking at protein-altering somatic single nucleotide variants, they similarly found dramatic differences between tumors. When they looked at intra-tumor heterogeneity, they found several instances where a clinically actionable mutation, such as PIK3CA p.H1047R, was found in some but not all of the subclones within a tumor, demonstrating the difficulty of choosing the best therapy on the basis of a single focus. The authors concluded that this study highlights a challenge of using molecular assays to profile tumors for prognostic and predictive biomarkers since specific clones within a tumor may yield very different results used to help guide patient care.
Boutros PC, Fraser M, Harding NJ, et al. Spatial genomic heterogeneity within localized, multifocal prostate cancer [published online ahead of print May 25, 2015]. Nat Genet. doi:10.1038/ng.3315.
Correspondence: Paul C. Boutros at paul.boutros@oicr.on.ca or Robert G. Bristow at rob.bristow@rmp.uhn.on.ca