A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns (original) (raw)
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Molecular and morphologic study of pancreatic cancer evolution
Molecular evolution of intraductal neoplasms CHAPTER 2 Pathology of pancreatic cancer precursor lesions CHAPTER 3 Genomic characterization of malignant progression in neoplastic pancreatic cysts CHAPTER 4 Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4 CHAPTER 5 IPMNs with co-occurring invasive cancers: neighbours but not always relatives CHAPTER 6 Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas PART 2 Three-dimensional histopathology through tissue clearing CHAPTER 7 A "clearer" view of pancreatic pathology: a review of tissue clearing and advanced microscopy techniques CHAPTER 8 Immunolabeling of cleared human pancreata provides insights into three-dimensional pancreatic anatomy and pathology CHAPTER 9 Three-dimensional visualization of cleared human pancreas cancer reveals that sustained epithelial-to-mesenchymal transition is not required for venous invasion CHAPTER 10 Why is pancreatic cancer so deadly? The pathologist's view PART 3 Pancreatic neuroendocrine neoplasms CHAPTER 11 Genetic analysis of small well-differentiated pancreatic neuroendocrine tumors identifies subgroups with differing risks of liver metastases CHAPTER 12 Whole-exome sequencing of duodenal neuroendocrine tumors in patients with neurofibromatosis type 1 CHAPTER 13 Well-differentiated pancreatic neuroendocrine tumor in a patient with familial atypical multiple mole melanoma syndrome (FAMMM) PART 4 Conclusion CHAPTER 14 Summarizing discussion CHAPTER 15 Nederlandse samenvatting PART 5 Appendix Curriculum Vitae
Distant metastasis occurs late during the genetic evolution of pancreatic cancer
Nature, 2010
Metastasis, 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 Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Evolutionary Origins of Recurrent Pancreatic Cancer
2019
Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that adjuvant or first-line platinum therapy corresponds to an increased mutational burden of recurrent disease. Recurrent disease is enriched for mutations that activate Mapk/Erk and PI3K/AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings advocate for combination therapies with immunotherapy and routine post...
Gastroenterology, 2013
BACKGROUND & AIMS: Increasing grade of pancreatic intraepithelial neoplasia (PanIN) has been associated with progression to pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that control progression from PanINs to PDAC are not well understood. We investigated the genetic alterations involved in this process. METHODS: Genomic DNA samples from lasercapture microdissected PDACs and adjacent PanIN2 and PanIN3 lesions from 10 patients with pancreatic cancer were analyzed by exome sequencing. RESULTS: Similar numbers of somatic mutations were identified in PanINs and tumors, but the mutational load varied greatly among cases. Ten of the 15 isolated PanINs shared more than 50% of somatic mutations with associated tumors. Mutations common to tumors and clonally related PanIN2 and PanIN3 lesions were identified as genes that could promote carcinogenesis. KRAS and TP53 frequently were altered in PanINs and tumors, but few other recurrently modified genes were detected. Mutations in DNA damage response genes were prevalent in all samples. Genes that encode proteins involved in gap junctions, the actin cytoskeleton, the mitogen-activated protein kinase signaling pathway, axon guidance, and cell-cycle regulation were among the earliest targets of mutagenesis in PanINs that progressed to PDAC. CONCLUSIONS: Early stage PanIN2 lesions appear to contain many of the somatic gene alterations required for PDAC development.
Molecular Alterations in Pancreatic Cancer: Transfer to the Clinic
International Journal of Molecular Sciences, 2021
Pancreatic ductal adenocarcinoma (PDA) is the most common cancer of the exocrine pancreas and probably the tumor that has benefited the least from clinical progress in the last three decades. A consensus has been reached regarding the histologic classification of the ductal preneoplastic lesions (pancreatic intra-epithelial neoplasia—PanIN) and the molecular alterations associated with them. Mutations in KRAS and inactivation of CDKN2A, SMAD4 and TP53 are among the most prevalent alterations. Next generation sequencing studies are providing a broad picture of the enormous heterogeneity in this tumor type, describing new mutations less prevalent. These studies have also allowed the characterization of different subtypes with prognostic value. However, all this knowledge has not been translated into a clinical progress. Effective preventive and early diagnostic strategies are essential to improve the survival rates. The main challenge is, indeed, to identify new effective drugs. Despi...
Genetic Evolution in the Metastatic Progression of Human Pancreatic Cancer Studied by CGH
Laboratory Investigation, 2001
Metastases are thought to be derived from emerging clones within primary tumors. Although the concept of the clonal evolution of cancer is well defined, the genetic grounds and significance of this process in human cancer progression are still poorly understood. To gain insight into the genetic basis and clonal evolution underlying the metastatic progression of human pancreatic cancer in vivo, we analyzed by comparative genomic hybridization (CGH) chromosomal imbalances in seven metastases originated in nude mice and their three corresponding orthotopically xenografted human pancreatic tumors. All metastases were found to be closely related to the corresponding orthotopic implant, adding many additional changes to the already altered copy number profile of the pancreatic tumors. Recurrent metastasis-specific alterations included gains at 16cen-q22 and 17q21-qter. CGH results from paired specimens strongly suggest that the majority of additional genetic alterations present in metastases are likely to be present in subclones in the primary tumor.
The patterns and dynamics of genomic instability in metastatic pancreatic cancer
2010
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 1-5 , 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 6,7 , including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites 7 , and how the tumour disseminates. Here we harness advances in DNA sequencing 8-12 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-Sphase 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.
Molecular Biology of Pancreatic Cancer
BioDrugs, 2001
The development of cancer involves the accumulation of genetic changes. Over the past decade there has a been spectacular advance in the knowledge of the genetic basis of cancer, mainly as a result of the rapid progression of molecular technology. Pancreatic cancer is one of the most lethal cancers. Conventional therapeutic approaches have not had much impact on the course of this aggressive neoplasm. Knowledge of the molecular biology of pancreatic cancer has grown rapidly. Genetic alterations in pancreatic cancer include oncogene mutations (most commonly K-ras mutations), and tumour suppressor gene alterations (mainly p53, p16, DCC, etc.