The patterns and dynamics of genomic instability in metastatic pancreatic cancer

Abstract

SUMMARY Pancreatic cancer is an aggressive malignancy with 5-year mortality of 97–98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations1–5, but genomic rearrangements have not been characterised in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours6,7, including phylogenetic relationships among metastases, the scale of on-going parallel evolution in metastatic and primary sites7, and how the tumour disseminates. Here, we harness advances in DNA sequencing8–12 to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-S phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than later stages of disease. Genomic instability frequently persists after cancer dissemination, resulting in on-going, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells; seeding metastasis may require driver mutations beyond those required for primary tumours; and phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, hewn by the tandem forces of genomic instability and evolutionary selection.

Reliable detection of subclonal single-nucleotide variants in tumour cell populations

“…In addition, the imbalances of SNP allele frequencies were used to correctly predict an LOH on chromosome 3 in only a subset of the tumour samples. Recent studies found genomic heterogeneity in breast cancer 10,24 , pancreatic cancer 25,26 , and B-cell chronic lymphocytic leukemia 9 , as well as mosaic amplifications of tyrosine kinase receptor genes in glioblastoma 27 . Together, these findings provide compelling evidence for clonal evolution as a general mechanism in cancer development.…”

Metabolic reprogramming of the tumor

“…With regard to the first, p53 is a tumor-suppressor protein that overhauls genome integrity by triggering cell-cycle arrest or apoptosis in response to DNA damage (Levine, 1997). More than half of human cancer types present mutations in the TP53 gene (Hollstein et al, 1991), probably because its normal activity would hamper the accumulation of genetic lesions needed for malignant progression (Campbell et al, 2010). Albeit TP53 knockout suffices to immortalize mouse cells (Carnero et al, 2000), no similar outcome has been observed in human cells unless they constitutively express telomerase, possibly owing to the shortness of human telomeres, which limits their lifespan (Hahn and Weinberg, 2002).…”

“…Destruction of tissue structure The acquisition of a fully malignant state encompasses the capacity to spread over the host organism and form secondary tumors, in a process called metastasis (Campbell et al, 2010). For solid cancers, invasion of normal tissue is the first step of this process.…”

“…It is generally assumed that intravasation and circulation of cancer cells to new seeding places involve single cancer cells (Giampieri et al, 2009;Campbell et al, 2010;Madsen and Sahai, 2010). Once in the blood stream, these circulating cells originating from pseudomesenchymal cells are exposed to the host immune system that may recognize them as damaged cells and consequently targets them for destruction.…”

Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor

“…Wnt-signaling pathway has also been shown to regulate the pancreatic β-cell endocrine function [36], proliferation, migration and differentiation [30]. Comprehensive genetic analysis [37][38][39] revealed that the Wnt is one of the six signaling pathways always altered in pancreatic cancers. [40] Its overexpression has recently been correlated to tumorigenesis, driving the self-renewal and differentiation of cancer stem cells and promoting the angiogenesis process [12,35,39,41,42].…”