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Whole genomes redefine the mutational landscape of pancreatic cancer.

Abstract

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Collaborators:

Biankin AV, Johns AL, Mawson A, Chang DK, Scarlett CJ, Brancato MA, Rowe SJ, Simpson SH, Martyn-Smith M, Thomas MT, Chantrill LA, Chin VT, Chou A, Cowley MJ, Humphris JL, Jones MD, Mead RS, Nagrial AM, Pajic M, Pettit J, Pinese M, Rooman I, Wu J, Tao J, DiPietro R, Watson C, Steinmann A, Ching Lee H, Wong R, Pinho AV, Giry-Laterriere M, Daly RJ, Musgrove EA, Sutherland RL, Grimmond SM, Waddell N, Kassahn KS, Miller DK, Wilson PJ, Patch AM, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Anderson M,Holmes O, Leonard C, Taylor D, Wood S, Xu C, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Newell F, Pearson JV, Bailey P, Quinn M,Nagaraj S, Kazakoff S, Waddell N, Krisnan K, Quek K, Wood D, Fadlullah MZ, Samra JS, Gill AJ, Pavlakis N, Guminski A, Toon C, Asghari R,Merrett ND, Pavey D, Das A, Cosman PH, Ismail K, O’Connnor C, Lam VW, McLeod D, Pleass HC, Richardson A, James V, Kench JG, Cooper CL,Joseph D, Sandroussi C, Crawford M, Gallagher J, Texler M, Forest C, Laycock A, Epari KP, Ballal M, Fletcher DR, Mukhedkar S, Spry NA, DeBoer B, Chai M, Zeps N, Beilin M, Feeney K, Nguyen NQ, Ruszkiewicz AR, Worthley C, Tan CP, Debrencini T, Chen J, Brooke-Smith ME, Papangelis V,Tang H, Barbour AP, Clouston AD, Martin P, O’Rourke TJ, Chiang A, Fawcett JW, Slater K, Yeung S, Hatzifotis M, Hodgkinson P, Christophi C,Nikfarjam M, Mountain A, Eshleman JR, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Hodgin M, Scarpa A,Lawlor RT, Beghelli S, Corbo V, Scardoni M, Bassi C, Tempero MA, Biankin AV, Grimmond SM, Chang DK, Musgrove EA, Jones MD, Nourse C,Jamieson NB, Graham JS, Biankin AV, Chang DK, Jamieson NB, Graham JS, Oien K, Hair J.

 

PMID: 25719666 [PubMed – indexed for MEDLINE] PMCID:PMC4523082

 

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.

Abstract

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2′-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.

Collaborators:

Biankin AV, Johns AL, Mawson A, Chang DK, Brancato MA, Rowe SJ, Simpson SL, Martyn-Smith M, Chantrill LA, Chin VT, Chou A, Cowley MJ, Humphris JL, Jones MD, Mead R, Nagrial AM, Pajic M, Pettit J, Pinese M, Rooman I, Wu J, Daly RJ, Musgrove EA, Sutherland RL, Grimmond SM, Waddell N, Kassahn KS, Miller DK, Wilson PJ, Patch AM, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu C, Nones K, Fink J, Christ A, Bruxner T, Cloonan N, Newell F, Pearson JV, Samra JS, Gill AJ, Pavlakis N, Guminski A, Toon C, Blankin AV, Asghari R, Merrett ND, Chang DK, Pavey DA, Das A, Cosman PH, Ismail K, O’Connor C, Lam VW, McLeod D, Pleass HC, James V, Kench JG, Cooper CL, Joseph D, Sandroussi C, Crawford L, Texler M, Forrest C, Laycock A, Epari KP, Ballal M, Fletcher DR, Mukhedkar S, Spry NA, DeBoer B, Chai M, Feeney K, Zeps N, Beilin M, Nguyen NQ, Ruszkiewicz AR, Worthley C, Tan CP, Debrencini T, Chen J, Brooke-Smith ME, Papangelis V, Tang H, Barbour AP, Clouston AD, Martin P, O’Rourke TJ, Chiang A, Fawcet JW, Slater K, Yeung S, Hatzifotis M, Hodgkinson P, Christophi C, Nikfarjam M, Eshleman JR, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Beghelli S, Corbo V, Scardoni M, Bassi C, Tempero MA, Scarlett CJ, Kaplan W, Scarpa A.

PMID: 22699621 [PUBMED – INDEXED FOR MEDLINE] PMCID: PMC3376394

Retrospective analysis of the utility of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in pancreatic masses, using a 22-gauge or 25-gauge needle system: a multicenter experience.

Abstract

BACKGROUND AND STUDY AIMS:

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is now performed routinely in many advanced endoscopy centers and has enhanced the ability to diagnose pancreatic masses. However, there is uncertainty about which needle size is optimal for EUS-FNA of pancreatic masses. We aimed to evaluate the performance of the 22-gauge and 25-gauge needles in obtaining cytologic diagnosis of pancreatic masses.

METHODS:

All cases that were referred for EUS-FNA for pancreatic masses between February 2001 and June 2007 were reviewed, and patients who underwent EUS-FNA using the 22-gauge and 25-gauge needle system were identified. In patients who underwent surgery, operative histopathological findings were compared with the cytopathological findings from EUS-FNA.

RESULTS:

A total of 842 patients with pancreatic masses detected on computed tomography (CT) and/or magnetic resonance imaging (MRI) and confirmed by EUS underwent EUS-FNA with the 22-gauge needle (n = 540) or the 25-gauge needle (n = 302). Results of EUS-FNA cytology findings were compared with the gold standard of surgical histopathological findings or long-term clinical follow-up. The sensitivity, specificity, PPV, and NPV of FNA were respectively 84%, 100%, 100%, and 73% [corrected] for the 22-gauge needle compared with 92%, 97%, 98%, and 87%, [corrected] respectively for the 25-gauge needle. No complications were noted in the 25-gauge needle group, compared with pancreatitis in 2% of the 22-gauge needle group.

CONCLUSIONS:

This retrospective comparative study shows that EUS-FNA with a 25-gauge needle system is a safe and reliable method for tissue sampling in pancreatic masses. The system is more sensitive and has a slightly [corrected] higher NPV than the standard 22-gauge needle. Our study suggests that perhaps the smaller caliber FNA needle causes less trauma during EUS-FNA and hence less complications. Further studies including randomized trials are needed.

Authors:

Yusuf TE, Ho S, Pavey DA, Michael H, Gress FG.

Endoscopy. 2009 May;41(5):445-8. doi: 10.1055/s-0029-1214643. Epub 2009 May 5. Erratum in: Endoscopy. 2009 Jun;41(6):509.

PMID: 19418399 [PubMed – indexed for MEDLINE]

 

Endoscopic therapy for upper-GI vascular ectasias

Abstract

BACKGROUND:

Upper-GI vascular ectasias, including angiodysplasia and gastric antral vascular ectasia may present with either acute or chronic bleeding. Endoscopic thermal modalities have been used to control acute bleeding and reduce transfusion requirements.

METHODS:

Endoscopic experience was reviewed for a 6-year period during which 32 patients requiring blood transfusions for upper-GI angiodysplasia or gastric antral vascular ectasia were evaluated. Patients seen during the first 5 years were treated with either Nd:YAG laser photocoagulation or multipolar electrocoagulation. During the most recent 12 months, all patients were treated by argon plasma coagulation. Response to therapy was assessed by change in mean Hb and transfusion requirements.

RESULTS:

Overall, 16 patients were treated by laser photoablation alone; 9, argon plasma coagulation with or without laser; and 7, multipolar electrocoagulation with or without laser. Mean follow-up for all patients was 19 months. After therapy, mean Hb concentration rose from 76 to 114 g/L for patients with gastric antral vascular ectasia and from 85 to 118 g/L for those with angiodysplasia. Endoscopic therapy abolished or reduced transfusion requirements in 93% of patients with gastric antral vascular ectasia and 76% with angiodysplasia. Patients with gastric antral vascular ectasia required a mean of 6 treatment sessions, while those with angiodysplasia required one to two sessions.

CONCLUSIONS:

Endoscopic thermal ablation effectively controls acute bleeding and reduces transfusion requirements in most patients with upper-GI vascular ectasias. Patients with gastric antral vascular ectasia require significantly more treatment sessions to achieve this effect.

Authors:

Pavey DA, Craig PI.

PMID: 14745397 [PubMed – indexed for MEDLINE]

Whole genomes redefine the mutational landscape of pancreatic cancer.

Abstract

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

PMID: 25719666 [PubMed – indexed for MEDLINE] PMCID: PMC4523082

Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas).

Abstract

OBJECTIVES:

Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality.

DESIGN:

Retrospective multinational study including SCN diagnosed between 1990 and 2014.

RESULTS:

2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN’s related mortality was 0.1% (n=1).

CONCLUSIONS:

After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN.

TRIAL REGISTRATION NUMBER:

IRB 00006477.