Pancreas Cancer Genomics
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- Clemence Baldwin
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1 Pancreas Cancer Genomics Steven Gallinger MD, MSc, FRCS HPB Surgical Oncology Program University Health Network Samuel Lunenfeld Research Institute Mount Sinai Hospital University of Toronto
2 Fate of the Next 100 Pancreas Cancer Patients t 100 Pancreas Cancer Patients Operable Not Operable 2-3 Five Year Survivors
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4 Whipple Reconstruction
5 Survival Total/123 Rate 5 year Survivors % 10 year Survivors %
6 Pancreatic Cancer Survival
7 Pancreatic Cancer - Histology
8 Somatic Mutations in Pancreatic Cancer Gene or Region Frequency of Alteration (% of tumors) K-ras >90 p16 >95 p DPC4 55 Chromosome 19q/AKT Chromosome 6q/MYB 10 Chromosome 20q/AIB1 10 BRCA LKB1/STK11 4 MKK4 4 TGF-β R-I or R-II <5 RB1 <5 Kern S. Molecular genetic alterations in ductal pancreatic adenocarcinomas. Med Clin North Am 2000(84):
9 Pancreas Cancer Xenograft
10 OICR International Cancer Genome Consortium Pancreatic Cancer Genome Project * BioBank Cancer Genomics Platform Bioinformatics ICGC DCC Expression Epigenetics Xenograft - sample purity and quantity - treatment model Sequencing Structural variants Copy number Exome Transcriptome Signatures and Targets - detection - treatment Validation
11 Pancreatic cancer: Causes Environmental factors Smoking Alcohol Coffee Diet Chemicals Host factors Past medical history Pancreatitis Genetic Predisposition Familial Aggregation of cases Familial cancer syndromes
12 Family History ~5-10% of pancreatic cancer is hereditary known hereditary cancer syndromes familial pancreatic cancer (FPC)
13 Known Hereditary Syndromes Syndrome Gene Estimated risk of pancreas cancer Hereditary Breast/Ovarian Cancer BRCA2 BRCA1 5-7% 2-3% Familial Atypical Multiple Mole Melanoma (FAMMM) CDKN2A 5-8% p16-leiden mutation ti ~15-20% Peutz-Jeghers Syndrome STK % (PJS) Hereditary Pancreatitis PRSS1/SPINK1 40%
14 Pancreas Cancer Genetics Program Familial GI Cancer Registry - MSH NCIC - Moore/Narod/Gallinger OCRN - Ontario Pancreas Cancer Study (OPCS) Moore/Urbach/Cotterchio/Gallinger PACGENE - NIH - Gallinger Expansion of OPCS - clinic-based recruitment - Liu (PMH) - Zane Cohen Digestive Disease Centre - Hung (MSH)
15 Melanoma + Pancreas Cancer
16 Breast/Ovarian Cancer + Pancreas Cancer
17 BRCA2 LOH AT AN AT AN D17S855 D17S856
18 Familial Pancreatic Cancer
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20 Novel Germline Translocation in a Young Pancreatic Cancer Patient
21 Localization of Translocation with Fluorescent in Situ Hybridization (FISH)
22 Germ-line DNA Copy Number Variation(CNV)
23 Role of Genetic Variation in Disease
24
25 PACGENE subjects subjects Mayo, Mayo, Ontario, Ontario, MDACC, MDACC, Karmanos, Nebraska, Nebraska Karmanos
26 CNVs Validated by qpcr CNV 464: Chr 12 CNV 439: Chr 12 CNV 487: Chr 13 CNV 10: Chr 1 CNV 310: Chr 8 CNV 131: Chr 3 CNV 421: Chr 11 CNV 27: Chr 1 CNV 216: Chr 5 Validated by Sara Validated by Aaron & Sara Validated by Aaron
27 CNV 464 Focus Region Chr Start End Size NSP &STY SNPs Algorithm Chip dechip/ cnag/ cnat/ Nsp/sty Genes mrna EST mirna Nearest Gene Cont Cases n y y n SFRS8 n 1
28 CNV Copy Number Re elative OFCCR Control Panc Cancer Case OFCCR Control OFCCR Control
29 Survival Analysis Mean Univariate i Multivariate i t Survival Analysis Analysis (months) Jaundice Yes 9 No p<0.05 Tumour size p< Lymph Node Pos Neg p<0.005 Stage p<0.01 p<0.01 Grade Well Mod Poor p<0.003 p<0.003
30 Pancreas Cancer Screening Program MSH/UHN Yearly transabdominal US and MRI Blood sampling for future biomarkers Psychosocial questionnaires Epidemiological questionnaires Genetic counselling
31 Eligibility Criteria 1) FPC ( 2 relatives in the same lineage with panc ca) 2) BRCA2 or p16 carriers (fam hx of panc ca not required) 3) BRCA1 carriers (fam hx of panc ca required) 4) relatives of pts with multiple cancers (one is panc ca) 5) PJS 6) hereditary pancreatitis th th t d f age 50, or 10 years younger than the youngest dx of panc ca in the family for criteria 1-4, age 25 for PJS, and age 35 for individuals with HP
32 Study Participants 241 recruited since % female average age 53 (range 22-87) 1/3 of participants travel > 100km to participate at their own expense.
33 Case 1: Pancreas Adenocarcinoma 57yo female with FPC 1.5cm mass total pancreatectomy based on local invasion and ductal atypia. Invasive adenocarcinoma, with multifocal PanINs 1/3 and one positive node. alive 14 months post-op Panc ca Dx: 66 Panc ca Dx: 62
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35 Case 4: PanIN 54yo female with FPC 1.5 x 0.7cm multilobulated cystic lesion body/tail, 0.6cm cyst in the panc tail, and a third 0.3cm cystic lesion in panc tail. Distal pancreatectomy. t Panc ca Dx: 78 PanIN1-2 Uterine ca Panc ca Dx: 53 Dx: 48
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