Genomic Analysis of Pancreatic Cancers Reveals Punctuated Evolution

Pancreatic cancer progression has been described by a classic progression model based on stepwise acquisition of genetic alterations that have been ordered based on the analysis of precursor lesions called pancreatic intraepithelial neoplasms (PanIN). However, tumors do not always appear to share the same lineage as PanINs, and although this model predicts a gradual cancer progression, the rapid progression to overt metastasis suggests the progression is not gradual. To determine how the high levels of genomic instability often exhibited by pancreatic cancers arise, Notta and colleagues analyzed whole genomes from over 100 primary and metastatic pancreatic tumors to identify mutational phenomena associated with rapid tumor progression. Polyploidy was observed in 48/107 tumors (45%), 42 of which were tetraploid and 6 of which were hexaploid. Polyploid tumors had more copy-number alterations and were more likely to harbor TP53 mutations than diploid tumors, and had increased loss of genetic material, indicating genomic instability. Mutations tended to precede the development of polyploidy, whereas most copy-number changes occurred after, but quickly became dominant within the tumor, suggesting that copy-number changes are more relevant to disease progression. The majority of tumors had at least one chromothripsis event. Chromothripsis was more common in polyploid tumors and frequently resulted in loss of SMAD4, gain in the region of GATA6, or amplification of KRAS, events associated with pancreatic tumorigenesis. Further, patients whose tumors exhibited chromothripsis had poorer overall survival. Overall, analysis of individual patients revealed that in the majority of polyploid tumors chromothripsis preceded polyploidy and metastasis. Moreover, analysis of the evolution of several tumors revealed simultaneous loss of several tumor suppressor genes that the PanIN model predicts would occur sequentially. Taken together, these findings suggest that some pancreatic tumors do not progress according to the stepwise PanIN model, and instead chromothripsis promotes transformation via a punctuated clonal evolution.

Notta F, Chan-Seng-Yue M, Lemire M, Li Y, Wilson GW, Connor AA, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 2016;538:378–82.