Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma

Connor, Ashton A.; Denroche, Robert E.; Jang, Gun Ho; Timms, Lee; Kalimuthu, Sangeetha; Selander, Iris; McPherson, Treasa A.; Wilson, Gavin; Chan-Seng-Yue, Michelle; Borozan, Ivan; Ferretti, Vincent; Grant, Robert C.; Lungu, Ilinca M.; Costello, Eithne; Greenhalf, William; Palmer, Daniel H.; Ghaneh, Paula; Neoptolemos, John P.; Büchler, Markus W.; Petersen, Gloria M.; Thayer, Sarah P.; Hollingsworth, Michael A.; Sherker, Alana; Durocher, Daniel; Dhani, Neesha C.; Hedley, David W.; Serra, Stefano; Pollett, Aaron; Roehrl, Michael H. A.; Bavi, Prashant; Bartlett, John M.S.; Cleary, Sean P.; Wilson, Julie M.; Alexandrov, Ludmil B.; Moore, Malcolm J.; Wouters, Bradly G.; Mcpherson, John Douglas; Notta, Faiyaz; Stein, Lincoln; Gallinger, Steven

doi:10.1001/jamaoncol.2016.3916

Cited by 230 publications

(224 citation statements)

References 59 publications

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“…The 4 most frequently altered genes in PDAC, i.e., KRAS (90%), TP53 (60-70%), CDKN2A (40-50%), and SMAD4 (30-40%), have long been known, and whole exome or genome analysis did not reveal new key driver genes with a frequency above 20%, confirming the important mutational landscape heterogeneity of PDAC [17][18][19][20][21]. None of these frequently mutated genes individually defines a clear subtype, although some, like CDKN2A, SMAD4, or MYC, have been shown to have a prognostic impact [22][23][24].…”

Section: Genomic Pdac Subtypesmentioning

confidence: 83%

“…Otherwise, these high-throughput analyses have defined 4 subtypes at the genome level: (i) a stable subtype (20%) with less than 50 structural variations, (ii) a locally rearranged subtype (30%) with significant focal events located on 1 or 2 chromosomes, (iii) a scattered subtype (36%) with widely distributed nonrandom chromosomal damage (<200), and (iv) an unstable subtype with extended (>200) structural variations [19]. Based on published mutational signatures, Connor et al [21] identified 4 main PDAC subtypes that partially overlap with those described above: (i) an age-related subtype (70%), (ii) a double stand break repair group (11%) that partially overlaps with the unstable subtype, (iii) a mismatch repair group (2%), and (iv) a group of unknown etiology. While these subtypes cannot be easily defined in routine practice, they may have an important theranostic value.…”

Section: Genomic Pdac Subtypesmentioning

confidence: 99%

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Tumor Heterogeneity in Pancreatic Adenocarcinoma

et al. 2017

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Pancreatic adenocarcinoma is one of the deadliest malignancies worldwide, mainly due to frequent diagnosis at an advanced stage and its strong chemoresistance. Tumor heterogeneity is evident at the histological level, both between tumors and even within a tumor. Recent high-throughput analyses have confirmed that intertumor heterogeneity is greater than intratumor heterogeneity that is mostly driven by successive catastrophic genetic events in the early stage and by epigenetic modifications in the metastatic stage. While this heterogeneity may complicate the search for a universal cure, these analyses have distinguished several subtypes at the genomic, transcriptomic, and metabolomic levels that offer, for some, new therapeutic opportunities.

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Section: Genomic Pdac Subtypesmentioning

confidence: 83%

Section: Genomic Pdac Subtypesmentioning

confidence: 99%

Tumor Heterogeneity in Pancreatic Adenocarcinoma

et al. 2017

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“…platinum-based chemotherapy, or to radiation therapy [84,85]. Moreover, this subtype of PDAC exhibits synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibitors and might be prone to sensitivity against immune checkpoint inhibitor therapy [86,87,88,89]. Since this is probably one of the most promising concepts for the development of novel therapeutic strategies against PDAC currently being followed, this topic is covered in a separate article of this minireview series.…”

Section: Novel Therapeutic Targetsmentioning

confidence: 99%

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

Feldmann¹

2018

Oncol Res Treat

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Pancreatic ductal adenocarcinoma (PDAC, pancreatic cancer) carries one of the poorest overall prognoses of all human malignancies known to date. Despite the introduction of novel therapeutic regimens, the outcome has not markedly improved over the past decades, the incidence rates are almost identical to the mortality rates, and PDAC is projected to soon become the second most common cause of cancer-related mortality in Western countries. Despite this clear medical need to develop novel therapeutic strategies against this dire malady, this need has so far not been addressed with sufficient institutional attention and support in terms of research funding and strategical programs. Given the still growing life expectancy and projected demographic changes with a growing proportion of senior citizens in many European societies, this discrepancy is likely to become even more pressing in the future. This article provides a brief overview of ongoing preclinical efforts to identify novel targets and, based on this, to develop novel strategies to treat advanced pancreatic cancer and improve survival and the quality of life of patients suffering from this malignancy.

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“…First, Connor et al, while noting the potential role of immune checkpoint inhibition in specific PDA subtypes, concluded that their classification featured no clinical implications [13]. On the other hand, Bailey et al identified and validated four major pancreatic cancer subclasses, which were associated with distinct histopathologic and clinical characteristics.…”

Section: Genome Sequencing Technologies and Potential Biomarkersmentioning

confidence: 99%

Prediction of Pancreatic Cancer Risk and Therapeutic Response with Next-Generation Sequencing

et al. 2017

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The overall 5-year survival rates of 8% [1] reflect the grim prognosis of patients with pancreatic ductal adenocarcinoma (PDA), which is at least partially explained by the unfruitful efforts to identify prognostic and predictive biomarkers toward tailored and optimized therapeutic interventions. Extensive heterogeneity at the level of molecular-signaling pathways [2,3], high metastatic capacity and significant therapeutic resistance suggest the need for a strategic shift to screening and early detection, as well as the development of more effective, novel systemictargeted therapies. This opinion article summarizes the potential of next-generation sequencing (NGS) and the emerging challenges in completing the catalog of cancer-driver genes (CDGs) for pancreatic cancer, detecting high-risk individuals through intensive screening and predicting drug response.Nevertheless, a recent, large-scale study by Bailey et al. [4], implementing whole-genome sequencing (WGS) and RNA sequencing (RNAseq) in an outstanding innovative design, has finally demonstrated significant clinical implications.The development of robust biomarkers is crucial to personalize and improve poor outcomes in patients with pancreatic cancer. However, no progress has been made in biomarker-based individualized preventive and therapeutic approaches, with 5-year survival rates remaining low, even in the early, localized disease stages [1].Despite the guidelines composed by national and international organizations prompting PDA patient enrollment in clinical trials, research has featured very slow progress in this area. More specifically, the lack of both effective targeted drugs and biomarkers-directed agents raises questions on whether a strategy of conventional clinical trial designs and traditional technology is able to alter the grim survival of PDA [5].The advent of NGS technologies about a decade ago and the development of umbrella and basket clinical trial designs integrating NGS [3] pave new avenues toward the precise biomarker-based prevention and treatment of pancreatic cancer. To this direction, recent large-scale genomic studies combining WGS and RNAseq have provided promising data and clinical implications on PDA prognosis and molecular classification [4,6].Precise prediction: an unmet clinical need Several environmental risk factors have been associated with pancreatic cancer. These include smoking, heavy alcohol consumption and chronic pancreatitis, exposure to specific chemicals and heavy metals, increased BMI and decreased physical activity, increased consumption of red and processed meat and dairy products, hepatitis B infection, diabetes mellitus, prediabetes, insulin and sulfonylureas [5]. It is worth noting that PDA patients with diabetes have a lower overall survival, compared with nondiabetics [7].Apart from the environmental effect on pancreatic tumorigenesis, pancreatic cancer has a familial component in 10% of cases and familial PDA excess, as well as earlier onset, increases the risk of cancer [8]. Nevertheless,

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Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma

Abstract: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.

Cited by 230 publications

References 59 publications

Tumor Heterogeneity in Pancreatic Adenocarcinoma

Tumor Heterogeneity in Pancreatic Adenocarcinoma

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

Prediction of Pancreatic Cancer Risk and Therapeutic Response with Next-Generation Sequencing

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