A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns

Abstract

Pancreas cancer (PC), a highly aggressive tumour type with uniformly poor prognosis, is an exemplar of the classical view of cancer development based on stepwise progression1. The current progression model, based on analyses of precursor lesions termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: 1) PC develops through a particular sequence of genetic alterations2–5 (KRAS > CDKN2A > TP53/SMAD4); and 2) the evolutionary trajectory of PC progression is gradual because each alteration is acquired independently. One shortcoming of this nearly two decade old contention is that clonally expanded precursor lesions have been identified that do not always belong to the tumour lineage2,5–9, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing view of tumourigenesis has contributed to the clinical notion that PC evolves slowly and presents at a late stage10. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes despite efforts aimed at early detection11, argue that PC progression is anything but gradual. By tracking DNA copy number changes and their associated rearrangements from tumour-enriched genomes using novel informatics tools, we found that PC tumourigenesis neither is gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory12. In a subset of cases, the consequence of such errors was the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that likely set-off invasive cancer growth. These findings challenge the current model of PC tumourigenesis and provide novel insights into the mutational processes giving rise to these aggressive tumours.

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

“…Large-scale chromosomal alterations may have profound impact upon the genome, disrupting hundreds of genes and can be considered macro-evolutionary events (see below), which may be required for tumor transformation (Notta et al, 2016). Loss of genomic material through chromosomal instability may also contribute to mutational ITH (McPherson et al, 2016;Murugaesu et al, 2015), highlighting the importance of considering both copy number and mutation data when inferring the evolutionary history of tumors.…”

“…Chromothripsis, characterized as a single catastrophic event resulting in tens of hundreds of locally clustered rearrangements affecting one or a few chromosomes, has also been documents to be widespread in cancers, occurring in over 30% of bladder cancers (Morrison et al, 2014), lung adenocarcinomas (Malhotra et al, 2013), oesophageal adenocarcinomas (Nones et al, 2014), glioblastomas (Malhotra et al, 2013), uterine leiomymoas (Mehine et al, 2013) and pancreatic cancers (Notta et al, 2016). These events occurred both clonally and subclonally during tumor evolution.…”

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

“…In the last three decades, the discovery of oncogenes and tumorsuppressor genes resulted in an improved understanding of how genetic events cause cancer, and dramatically shifted the approaches used to develop new cancer therapies (3,4). The realization that cancer relies on mutations to corrupt existing pathways controlling development, cell growth, and proliferation suggested these same pathways might be targeted to treat cancer (5,6).…”

A Simple Way to Reduce the Risk of Cancer of the Oral Cavity, Pharynx, Larynx and Esophagus in Alcohol Users

“…For example, cell division generates spontaneous mutations arising during DNA replication [9]; it has been estimated that three mutations may occur every time a normal stem cell divides [10,11]. Cell division can also generate chromosome aberrations occurring during mitosis [12][13][14][15][16]; chromosome segregation errors can lead to mutations and chromosome rearrangements that integrate into the genome [13,14]. These DNA alterations can affect oncogenes and tumor-suppressor genes and disorder genetic programs controlling stem cell behavior and fate.…”