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Pancreatitis and Pancreatic Cancer

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  1. Pancreatitis and Pancreatic Cancer David C Whitcomb MD Ph.D. Professor of Medicine, Cell Biology & Physiology and Human Genetics Chief, Division of Gastroenterology, Hepatology and Nutrition Director, Center for Genomic Sciences University of Pittsburgh

  2. Outline 1. Origins of Pancreatitis Premature trypsinogen activation 2. Genetics of Acute and Chronic Pancreatitis Trypsinogen SPINK1 CFTR 3. Pancreatic Cancer Links with pancreatitis

  3. Pancreas Anatomy

  4. Histology Duct Islet Acinus fat

  5. Pancreas Pancreatitis • Pancreas - an organ that makes bicarbonate to nutralize gastric acid, enzymes to digest the contents of a meal and insulin to signal the body to store ingested nutrients. • Acute Pancreatitis- An acute, potentially life-threatening condition presenting with severe abdominal pain in which the pancreas appears to digest itself. It is usually caused by gallstones, alcohol or is idiopathic. • Chronic Pancreatitis - an irreversible scarring of the pancreas with permanent loss of pancreatic function that typically causes unrelenting abdominal pain. • Hereditary Pancreatitis - a unusual form of acute and chronic pancreatitis that runs in families. The risk of pancreatic cancer is >50 times normal.

  6. CT of Pancreatic Necrosis

  7. CT of Severe Chronic Pancreatitis

  8. Chronic Pancreatitis: 1995 Medical Progress: Chronic Pancreatitis. Volume 332(22) 1 Jun 1995 pp 1482-1490 Michael L Steer, Irving Waxman, Steven Freedman “chronic pancreatitis remains an enigmatic process of uncertain pathogenesis, unpredictable clinical course, and unclear treatment”

  9. Origins of Pancreatitis • Pre-1896: Pancreatitis is an infection • 1896: Pancreatitis is pancreas autodigestion • 1996: Hereditary Pancreatitis is caused by mutations in the cationic trypsinogen gene (PRSS1)

  10. Hereditary Pancreatitis Pancreas • Hereditary pancreatitis (HP) is an unusual form of acute and chronic pancreatitis that runs in families. The risk of pancreatic cancer is >50 times normal. • Although HP is only responsible for 2-3% of all cases of chronic pancreatitis, study of this disease has revolutionized our understanding of pancreatic diseases

  11. E-mail • Dear Dr.Whitcomb, • Hi, the Doctors think I have hereditary pancreatitis because my dad has it too. I don't really know much about it except that it hurts in your back, sides and stomachs areas. (speaking from experience) I've been in the hospital once for it because it was the worst attack I've had. If you could send me more information on it, it would be greatly appreciated. By the way I'm 12, just in case it matters. My dad's 42. • Have a nice day Dr.Whitcomb

  12. HP Kindred without 7q35 linkage A large family was identified through self-referral Seventy-one members Six affected Two obligate carriers

  13. Linkage of HP to Chromosome 7q35 Whitcomb et al. GASTROENTEROLOGY 110:1975, 1996 0.00001 5 Chromosome 7 4 0.0001 0.001 3 0.01 2 0.1 1 LOD Scores 0 Cystic Fibrosis Gene (P value) Hereditary Pancreatitis Gene HP GENE -5 D7S523 D7S483 D7S461 D7S495 D7S684 D7S661 D7S550 D7S559 D7S505 TCRB Markers on chromosome 7

  14. 2. Genetic Mapping 3. Mutation 4. Mechanism ccaccaccagtcaggcacactctaccaccATGAATCCACTCCTGATCCTTACCTTTGTGG/ACAGCTGC TCgtgagtatcatgccctgcctcaggccccaaccacccccccgttcctggccga Hereditary Pancreatitis gene Trypsinogen DNA Mutation in the trypsinogen DNA sequence Functional significance determined Chromosome 7 Discovery of the Pancreatitis Gene Whitcomb et al 1996 1. Family Recruitment

  15. Physiology of Trypsin Solid Food Solid Food TRYPSIN Enterokinase Trypsinogen Chymotrypsinogen Proelastase Procarboxypeptidase Proenzymes Trypsin Chymotrypsin Elastase Carboxypeptidase Enzymes Liquid

  16. Trypsin - Trypsin - - - Trypsin PSTI PSTI H122 Enzymes Proenzymes ? Autodigestion Pancreatitis Fail-safe Trypsin Inactivation Trypsinogen - + (Autoactivation) Trypsin (wt) R122 Whitcomb et al, Nature Genetics 1996

  17. Ferec 1999 Gorry 1997 Teich 2000 Witt 1999 APFDDDDKIVGGYNCEENSVPYQVSLN Pfutzet 1999 (+CFTR R117H) Whitcomb 1996 Trypsinogen Alignment & Mutations Whitcomb MCNA 2000 Exon 1signal peptide CODON 1 10 14 | | | CT MNPLLILTFVAAAL AT MNLLLILTFVAAAV MT MNPFLILAFVGAAV Chy MAFLWLLSCWALLGTTF Exon 2 TAP CODON 15 16 23 29 40 50 60 67 | | | | | | | | CT AAPFDDDDKIVGGYNCEENSVPYQVSLNSGYHFCGGSLINEQWVVSAGHCYKS AT A APFDDDDKIVGGYICEENSVPYQVSLNSGYHFCGGSLISEQWVVSAGHCYKS MT AVPFDDDDKIVGGYTCEENSLPYQVSLN SGSHFCGGSLISEQWVVSAAHCYKT Chy GCGVPAIHPVLSGLSRIVNGEDAVPGSWPWQVSLQDKTGFHFCGGSLISEDWVVTAAHCGVR | | || | | | | Chy# 1 10 2021 30 40 50 57 Exon 3 CODON 68 70 80 90 100 110 120 122 130 140 150 152 | | | | | | || | | | | CT RIQVRLGEHNIEVLEGNEQFINAAKIIRHPQYDRKTLNNDIMLIKLSSRAVINARVSTISLPTAPPA TGTKCLISGWGNTASSGA AT RIQ VRLGEHNIEVLEGNEQFINAAKIIRHPKYNSRTLDNDILLIKLSSPAVINSRVSAISLPT APPA AGTESLISGWGNTLSSGA MT RIQ VRLGEHNIKVLEGNEQFINAAKIIRHPKYNRDTLDNDIMLIKLSSPAVINARVSTISLPT APPA AGTECLISGWGNTLSFGA Chy TSDVVVAGEFDQGSDEENIQVLKIAKVFKNPKFSILTVNNDITLLKLATPARFSQTVSAVCLPSADDDFPAGTLCATTGWGKTKYNAN | | | | | | | | | | | Chy# 62 70 80 90 100102 110 117 120 130 140

  18. PRSS1 Mutations - Overview • Two mutations are both common and disease-causing: PRSS1 R122H and N29I (new numbers) • Individuals with either of the two mutations have about an 80% chance of developing acute pancreatitis. • Of those with acute pancreatitis, about half develop chronic pancreatitis • 40% with chronic pancreatitis will develop pancreatic cancer by age 70 (smoking doubles risk)

  19. Changes human to porcine SPINK1/PSTI Alignment & Mutations Pfutzer et al, Gastroenterology, 2000 Comparison of human , porcine and rat , SPINK1/PSTI. Obs var; observed variations in human protein sequence deduced from allele polymorphisms. *; the “bait” lysine (K) in human and porcine, and arginine (R ) in rat that projects into the specificity pocket of trypsin during trypsin inhibition. Homology between human and porcine SPINK1 (PSTI) is 71% Exon 1Exon 2 Codon # 1 10 18 24 29 obs var | | P | | | human MKVTGIFLLSALALLSLS* GNTGADSLGRE * Porcine TSPQRE rat MKVAIIFLLSALALLNLA GNTTAKVIGKK | | Peptide # 1 6 Exon 3 Codon # 30 34 40 50 55 60 65 obs var | S |* E S | | humanAKCYNELNGCTKIYDPVCGTDGNTYPNECVLCFENR * * porcineATCTSEVSGCPKIYNPVCGTDGITYSNECVLCSENK ratANCPNTLIGCPRDYDPVCGTDGKTYANECILCFENR | | | | | | Peptide # 7 11 20 30 40 42 Exon 4 Codon # 66 70 79 obs var | | | human KRQTSILIQKSGPC porcine KRQTPVLIQKSGPC rat KFGTSIRIQRRGLC | | | Peptide # 43 50 56

  20. SPINK1 / PSTI N34S Mutation Pfutzer et al, Gastroenterology, 2000 • Superposition of the porcine SPINK1 structure (blue) on the human (modified for chymotrypsin specificity) SPINK1 structure (red). Model by Andrew Brunskil & William F. Furey

  21. 100 90 80 ICP 70 SPINK1 N34S / N34S 60 SPINK1 N34S / P55S 50 40 30 20 10 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 SPINK1 Genotype-Phenotype Pfutzer et al, Gastroenterology, 2000 Cumulative Incidence of Pancreatitis SPINK1 N34S Affected (% total) Age of Symptom Onset (years)

  22. SPINK1 Mutations - Overview • SPINK1/PSTI mutations are common in the population (~2%) • SPINK1/PSTI are clearly associated with ICP (~25%). • The mutation associated risk is low (<1%). • Modeling and familial clustering suggest that SPINK1 mutations are disease modifying. • SPINK1/PSTI mutations may lower the threshold for pancreatitis from other genetic or environmental factors, but by themselves are not disease causing • The N34S mutations has a world-wide distribution.

  23. SPINK1 Mutations - Overview • SPINK1/PSTI mutations are common in the population (~2%) • SPINK1/PSTI are clearly associated with ICP (~25%). • The mutation associated risk is low (<1%). • Modeling and familial clustering suggest that SPINK1 mutations are disease modifying. • SPINK1/PSTI mutations may lower the threshold for pancreatitis from other genetic or environmental factors, but by themselves are not disease causing

  24. 80 70 60 50 40 30 20 10 0 Ever Smoked Never Smoked Smoking & Risk of Cancer in HP A.B. Lowenfels, P. Maisonneuve, D. C.Whitcomb, and the International Hereditary Pancreatitis Study Group Age at diagnosis of pancreatic cancer Risk of Pancreatic Cancer 150 100 50 0 Age (years) Relative Risk GP HP HP + Smoked