The patterns and dynamics of genomic instability in metastatic pancreatic cancer

By Peter J. Campbell, S. Yachida, L. Mudie, Philip J. Stephens, D. Erin, Pleasance, L. Stebbings, L. Morsberger, Calli Latimer, Stuart McLaren and 18 more. Nature, 2010

1,349 citations recorded by the source corpus.

Pancreatic cancer is an aggressive malignancy with a five-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 mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing 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-to-S-phase transition with intact G2–M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.

Subfields: Cancer Research, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/6ce49e152c1ca7c6a26716ceea3ef0f8d4dab250

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Citations in the corpus

Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma (2014, neutral): “In addition, some tumors have ‘‘fold-back intrachromosomal translocations’’ (Campbell et al., 2010) to inactivate tumorsuppressor genes (Figure S3).”
Chromothripsis and kataegis induced by telomere crisis (2015, neutral): “Suchevents havebeenobserved in pancreatic cancer, esophageal cancer, breast cancer, and leukemias, among others (Bignell et al., 2007; Campbell et al., 2010; Waddell et al., 2015; Li et al., 2014; Nones et al., 2014).”
Intratumor heterogeneity: evolution through space and time. (2012, background): “Conceivably, differences in tumor environmental selection pressures at metastatic sites may result in regional variation of tumor subclone evolution as distinct environments select for certain subclones over others, further contributing to ITH (11).”
Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer (2016, background): “loss of somatic mutations through subsequent genetic events is uncommon in the context of natural tumor evolution or therapeutic resistance (24-26).”
Cancer stem cells: impact, heterogeneity, and uncertainty. (2012, background): “In pancreatic cancer and medulloblastoma, genetically distinct subclones initiate metastatic disease (Campbell et al., 2010; Wu et al., 2012; Yachida et al., 2010).”
Cancer heterogeneity: implications for targeted therapeutics (2013, background): “There is now compelling evidence to support a branched evolutionary pattern of tumour growth across many haematological (Anderson et al, 2011) and solid tumours (Shah et al, 2009; Campbell et al, 2010; Yachida et al, 2010; Gerlinger et al, 2012; Wu et al, 2012).”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, positive): “…that were resected synchronously, while others have compared metastases sampled up to 17 years after resection of the corresponding primary tumors; both have found genetic similarities between the two tissues (Campbell et al., 2010; Ding et al., 2010; Haffner et al., 2013; Liu et al., 2009).”
Dynamics of genomic clones in breast cancer patient xenografts at single cell resolution (2014, neutral): “Cluster (n) 1 (60) 2 (23) 3 (15) 4 (14) 5 (13) 6 (11) 7 (9) 8 (6) 9 (5) 10 (5) 11 (3) 12 (3) 13 (2) 14 (2) 15 (1) 16 (1) 17 (1) 18 (1) 19 (1) 20 (1) 0.”
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Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets (2015, background): “Because cancers are genetically heterogeneous (3-9), sampling a cancer in two different locations is expected to reveal mutations exclusive to each sample.”