Comparing nodal versus bony metastatic spread using tumour phylogenies.

Stefano Mangiola,Matthew K H Hong,Natalie Kurganovs,Marek Cmero,Christopher M Hovens,Niall M Corcoran,Andrew Ryan,Geoff Macintyre,Anthony J Costello

doi:10.1038/srep33918

Abstract

The role of lymph node metastases in distant prostate cancer dissemination and lethality is ill defined. Patients with metastases restricted to lymph nodes have a better prognosis than those with distant metastatic spread, suggesting the possibility of distinct aetiologies. To explore this, we traced patterns of cancer dissemination using tumour phylogenies inferred from genome-wide copy-number profiling of 48 samples across 3 patients with lymph node metastatic disease and 3 patients with osseous metastatic disease. Our results show that metastatic cells in regional lymph nodes originate from evolutionary advanced extraprostatic tumour cells rather than less advanced central tumour cell populations. In contrast, osseous metastases do not exhibit such a constrained developmental lineage, arising from either intra or extraprostatic tumour cell populations, at early and late stages in the evolution of the primary. Collectively, this comparison suggests that lymph node metastases may not be an intermediate developmental step for distant osseous metastases, but rather represent a distinct metastatic lineage.

Highlights

It has long been recognized that the spread and seeding of metastatic tumour cells from the primary site of origin does not follow a random pattern, rather, there are characteristic anatomical sites favouring the formation of metastatic lesions[1]
In order to identify the patterns of copy number aberrations (CNAs) that emerged at the transition across histo-pathological categories, a combined evolutionary reconstruction and differential analysis of gene copy number was performed
In this study we explored the genomic relationships between distinct metastatic populations in a small number of advanced prostate cancer patients

Summary

Introduction

It has long been recognized that the spread and seeding of metastatic tumour cells from the primary site of origin does not follow a random pattern, rather, there are characteristic anatomical sites favouring the formation of metastatic lesions[1]. Recent clinical studies suggest that metastatic spread is a more complex process, and that tumour colonisation of regional lymph nodes may not directly contribute to lethality, but instead represent an evolutionary ‘cul-de-sac’ that may be a pathological marker of inherently aggressive disease but does not play a direct role in systemic colonisation[9] It remains to be clarified whether visceral metastases arise from previously established metastatic lymph nodes or if lymph nodes are irrelevant to the evolution of distant metastases. Tumour phylogenetic methods that permit the tracing of tumour cell lineages in human cancers have been used to identify the roots of metastasis in humans[16] and, along with mapping in a comprehensive manner the sub-clones within the primary tumour, has been stressed to be key for the reconstruction of the metastatic spread[17] These studies did not characterise localised lymph node metastases. We show lymph node metastases originated exclusively from evolutionarily advanced, extraprostatic regions of primary tumour, whereas distant metastases originated either from central (2 cases) or extraprostatic primary tumour regions (1 case)

Methods

Results

Conclusion