Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients

Sausen, Mark; Phallen, Jillian; Adleff, Vilmos; Jones, Siân; Leary, Rebecca J.; Barrett, Michael T.; Anagnostou, Valsamo; Parpart-Li, Sonya; Murphy, Derek; Li, Qing Kay; Hruban, Carolyn; Scharpf, Rob; White, James R.; O’Dwyer, Peter J.; Allen, Peter J.; Eshleman, James R.; Thompson, Craig B.; Klimstra, David S.; Linehan, David C.; Maitra, Anirban; Hruban, Ralph H.; Díaz, Luis A.; Hoff, Daniel D. Von; Johansen, Julia S.; Drebin, Jeffrey A.; Velculescu, Victor E.

doi:10.1038/ncomms8686

Cited by 411 publications

(366 citation statements)

References 30 publications

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“…Wholeexome sequencing studies (Jones et al 2008;Biankin et al 2012;Sausen et al 2015;Waddell et al 2015;Witkiewicz et al 2015;Bailey et al 2016) have reaffirmed the signature mutations of human pancreatic cancers, including near-ubiquitous oncogenic mutations of KRAS and the frequent inactivation of TP53, SMAD4, and CDKN2A tumor suppressors (Hezel et al 2006;Maitra and Hruban 2008;Hidalgo 2010;Vincent et al 2011;Ryan et al 2014). These unbiased analyses also identified additional novel recurrent mutations in PDAC; however, the prevalence of individual mutations drops sharply to ≤10%.…”

Section: The Pdac Genomementioning

confidence: 95%

“…Interestingly, MLL2/3 and KDM6A are present in the same complex, driving transcriptional activation through the coordinated regulation of H3K4 methylation and H3K27 demethylation (Lee et al 2007b). While the downstream targets of the MLL/ KDM6A machinery during PDAC development remain to be identified, tumors with MLL mutations tend to induce high expression of chromatin-regulating genes together with other genes involved in cell proliferation (Sausen et al 2015), suggesting that a genetic defect of MLL complexes likely leads to global epigenetic alterations to support tumor development.…”

Section: Pdac Epigeneticsmentioning

confidence: 99%

“…Among the mutated histone modification enzymes are the histone methyltransferases MLL, MLL2, and MLL3 and the histone demethylase KDM6A (Biankin et al 2012;Sausen et al 2015;Waddell et al 2015;Witkiewicz et al 2015). Interestingly, MLL2/3 and KDM6A are present in the same complex, driving transcriptional activation through the coordinated regulation of H3K4 methylation and H3K27 demethylation (Lee et al 2007b).…”

Section: Pdac Epigeneticsmentioning

confidence: 99%

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Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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Section: The Pdac Genomementioning

confidence: 95%

Section: Pdac Epigeneticsmentioning

confidence: 99%

Section: Pdac Epigeneticsmentioning

confidence: 99%

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Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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“…Other noninvasive serum approaches include the use of circulating tumor DNA (ctDNA). In a study of patients who underwent resection of their primary pancreatic tumor, the detection of ctDNA preceded the presence of measurable recurrent pancreatic cancer on CT by 9.9 months [72]. Other clinical studies have examined the use of urinary KRAS in advanced cancers requiring very small copy numbers of the KRAS ctDNA [73].…”

Section: Methods Of Early Detection Of Pancreatic Cancermentioning

confidence: 99%

Hereditary Pancreatic Cancer

Borazanci¹,

Haag²

2017

Challenges in Pancreatic Pathology

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Pancreatic cancer is estimated to surpass breast cancer to become the third leading cause of cancer-related death in the USA in 2016. The 5-year overall survival is 7%, and most individuals are diagnosed with advanced disease. Thus, there is a need to improve the early detection of pancreatic cancer in order to detect and improve survival in the same way that mammograms and colonoscopies have improved survival for individuals with breast and colorectal cancer. This chapter discusses the genetics of hereditary pancreatic cancer, the current available screening options, and the use of biomarkers for early detection of pancreatic cancer.

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“…For example, oncogenic KRAS mutations can be identified in up to 90% pancreatic cancers and occur early in the developmental progression from advanced pancreatic intraepithelial neoplasia to metastatic pancreatic cancer [8]. However, even forgoing the specificity concerns with KRAS mutation detection, studies of ctDNA in peripheral blood assessing for KRAS mutations in pancreatic cancer patients without distant metastases had detection rates of only 43-48% [9,10]. A recent report using a next-generation sequencing multigene panel in cfDNA of patients with pancreatic cancer was more promising (detecting over 90% of the mutations seen by tumor biopsy sequencing) [11].…”

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confidence: 99%