Distant metastasis occurs late during the genetic evolution of pancreatic cancer

Abstract

SummaryMetastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated 12, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemo- or radiation therapy 3. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

Early diagnosis of pancreatic cancer: Current trends and concerns

“…These observations should support a genetic progression model of pancreatic carcinogenesis leading to invasive cancer 5, 6, 7, 8, 9, 10. Recently, the estimated lifetime of clonal evolution during PC development and progression based on a computational model using many autopsy cases has been reported 11, 12. This model suggested an average of 11.7 years from the initiating carcinogenesis until development of the parental clone, an average of 6.8 years to the development of metastatic subclones within the primary PC, and an average of 2.7 years until death of the case (Figure 1).…”

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.…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…Thus, in addition to inter‐tumoral (or patient specific) variation, significant intra‐tumoral variation is evident in many tumor types, in forms spanning histological to genetic heterogeneity. Such variability may be reflective of regional foci of clonal evolution (Yachida et al., 2010), as well as tumor self‐seeding from disseminated cancer cells (Comen et al., 2011). Moreover, the heterogeneity of putative tumor‐initiating cells (or cancer stem cells) may contribute to subtype variation in certain solid tumor types, as suggested by studies employing mouse models of glioblastoma, intestinal, and prostate cancer (Visvader, 2011).…”

“…This figure is suspected to be an underestimation of the mutational landscape of individual tumors, as the analytic techniques that have been used most frequently, such as PCR‐based sequencing of DNA extracted from total tumor lysates, may not detect mutations occurring in subclonal tumor cell populations (Loeb, 2011; Sellers, 2011). This is illustrated, for example, by exomic sequencing of separate, histologically distinct regions micro‐dissected from individual human pancreatic ductal carcinomas (PDACs): each showed a specific mutational repertoire indicative of multiple subclonal populations within the same primary tumor (Yachida et al., 2010). Consistent with these findings, recent whole‐genome deep (or high‐throughput) sequencing analysis of individual tumors has revealed that a particular tumor specimen may contain up to 50,000 different non‐synonymous mutations affecting several hundred genes, with mutation rates of 0.5–20 per megabase (Loeb, 2011; Sellers, 2011).…”