Evolution and dynamics of pancreatic cancer progression

Abstract

Efficient metastasis is believed as the result of multiple genetic, epigenetic and/or post-translational events in the lifetime of a carcinoma. At the genetic level, these events may be categorized into those that occur during carcinogenesis, and those that occur during subclonal evolution. This review summarizes current knowledge of the genetics of pancreatic cancer from its initiation within a normal cell until the time that is has disseminated to distant organs, many features of which can be extrapolated to other solid tumor types. The implications of these findings to personalize genome analyses of an individual patient's tumor are also discussed.

Figure 1

Genetic progression model of pancreatic carcinogenesis. The molecular alterations that accumulate during pancreatic carcinogenesis can be classified into early (telomere shortening and activating mutations in KRAS in PanIN-1), intermediate (inactivating mutations or epigenetic silencing of CDKN2A in PanIN-2) and late (inactivating mutations of TP53 and SMAD4 in PanIN-3) events. Mutations in additional genes may also occur during PanIN formation that are not illustrated in this example. While the genetic events that correspond to pancreatic carcinogenesis have been well described, those that occur during progression remain unknown.

Figure 2

Core-signaling pathways in pancreatic cancer. The fourteen pathways and processes whose component genes were genetically altered in most pancreatic cancers based on whole exome sequencing are shown in light gray, and the two pathways more recently identified in pancreatic cancer in dark gray.^– Therapeutic targeting of one or more of these pathways, rather than specific gene alterations that occur within a pathway, provides a new paradigm for treatment of pancreatic cancer. GTPase, guanosine triphosphatase; TGFβ, transforming growth factor β.

Figure 3

Patterns of metastatic failure. (a) Representation of the anatomic structures surrounding the pancreas (P). Image provided courtesy of the Johns Hopkins Pancreatic Cancer Home page (www.path.jhu.edu/pancreas/). (b) At autopsy, patients with. oligometastatic pancreatic cancer have few metastases (0 to 10), and the cause of death is most often due to the large primary carcinoma that invades into adjacent vital structures such as the duodenum, stomach or large vessels. By contrast, approximately two thirds of patients have widely metastatic pancreatic cancer that is defined as >10 distant metastases. In reality, the number of metastases in these patients is in the tens to hundreds of deposits.

Figure 4

Clonal evolution of pancreatic carcinogenesis and progression. Red arrows indicate the lineage of the index metastasis from its origin in a normal cell. Carcinogenesis, and time T₁, begins with an initiating alteration (M) in a normal cell that provides a selective advantage. Over time, waves of clonal expansion occur in association with the acquisition of additional mutations in genes such as CDKN2A, TP53 or SMAD4, corresponding to the progression model of PanIN. This clonal expansion is expected to generate more than one subclone within a PanIN, one of which will give rise to the founder cell (blue clone) that will eventually become the parental clone and hence initiate the infiltrating carcinoma. The birth of this cell corresponds to the beginning of time T₂. Following additional waves of clonal expansion from the parental clone, subclones are again generated within the infiltrating carcinoma leading to genetic heterogeneity. The birth of the cell within the primary carcinoma that will become the metastatic subclone (green clone) corresponds to the start of time T₃. Whether a single metastatic subclone generates all metastases in a patient is currently unknown.

Figure 5

Clinical implications of subclonal evolution in pancreatic cancer. As discussed, pancreatic carcinogenesis follows the accumulation of both driver and passenger mutations culminating in the formation of the founder cell (blue clone) that will become the parental clone of the carcinoma. The parental clone that initiates the infiltrating carcinoma will continue to undergo clonal evolution, leading to the formation of subclones that differ in the presence of newly acquired mutations in the hypothetical genes α, β, γ and Δ. Should a therapy that targets the subclone with mutant β effectively clear all cancer cells containing that mutation, over time the remaining subclones will continue to grow and new subclones (for example, ε) will emerge.