Abstract
Genetics and immunologic dynamics pushing the evolution of colorectal cancer (CRC) from the primary tumor to the metastases are largely unknown; cancer heterogeneity makes challenging both therapy and mechanistic studies. We selected patients developing CRC with lung-limited metastatic disease as only illness during their life in order to find any relevant genotype–phenotype relationship. Analysis of 523 cancer-relevant genes and of immune cells infiltration in primary and metastatic tissues revealed atypical genomic trajectories (TMB decrease, KRAS and SMAD4 regressive mutations), specific genetic events (ERBB2 point mutations) and scarce T-cell infiltration. These insights provide novel information in oligometastatic CRC biology and new perspectives for cancer monitoring and anti-cancer therapeutic strategies.
Highlights
Colorectal cancer (CRC) is the third most frequent neoplasm and the second cause of cancer-related deaths worldwide[1,2]
Disease characteristics and genetic concordance From 2006 to 2016, 97 patients underwent to lung wedge resections for CRC oligometastases (1–3 nodules)
A strict selection of those patients was subsequently applied in order to identify CRC patients who developed a single metastasis and were free from disease recurrence at a minimum follow-up of three years after lung resection
Summary
Colorectal cancer (CRC) is the third most frequent neoplasm and the second cause of cancer-related deaths worldwide[1,2]. Identifying the genetic and immunologic events in determining the clinical behavior and the evolution of a neoplasm, Many studies in pMD of CRC and other cancers have revealed heterogeneous results in genetics of primary tumors (PT) and matched metastatic lesions (as evidenced by de novo variations) with concordance rates (shared point mutations/total number of point mutations) varying from 0 to 100% (median: 45%)[4,5,6,7,8] (Supplementary File S1). The last evidences suggest that, when genetically similar, the cancer might evolve via epigenetic or regulatory modifications otherwise, crucial genetic events might switch on the metastatic/aggressive phenotypes (uncontrolled and sustained proliferation, spread to distant specific organs, resistance to therapy, etc.). The timing as well as the clinical effects of such internal clash among altered
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