Pancreatitis and Pancreatic Cancer David C WhitcombDavid C Whitcomb MD Ph.D. David C Whitcomb...
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Transcript of Pancreatitis and Pancreatic Cancer David C WhitcombDavid C Whitcomb MD Ph.D. David C Whitcomb...
Pancreatitis and Pancreatic CancerPancreatitis and Pancreatic Cancer
David C WhitcombDavid C Whitcomb MD Ph.D. MD Ph.D.Professor of Medicine, Cell Biology & Physiology Professor of Medicine, Cell Biology & Physiology
and Human Geneticsand Human Genetics
Chief, Division of Gastroenterology, Hepatology Chief, Division of Gastroenterology, Hepatology and Nutritionand Nutrition
Director, Center for Genomic SciencesDirector, Center for Genomic Sciences
University University ofof Pittsburgh Pittsburgh
David C WhitcombDavid C Whitcomb MD Ph.D. MD Ph.D.Professor of Medicine, Cell Biology & Physiology Professor of Medicine, Cell Biology & Physiology
and Human Geneticsand Human Genetics
Chief, Division of Gastroenterology, Hepatology Chief, Division of Gastroenterology, Hepatology and Nutritionand Nutrition
Director, Center for Genomic SciencesDirector, Center for Genomic Sciences
University University ofof Pittsburgh Pittsburgh
OutlineOutline
1.1. Origins of PancreatitisOrigins of PancreatitisPremature trypsinogen activationPremature trypsinogen activation
2. 2. Genetics of Acute and Chronic PancreatitisGenetics of Acute and Chronic PancreatitisTrypsinogenTrypsinogen
SPINK1SPINK1
CFTRCFTR
3.3. Pancreatic CancerPancreatic CancerLinks with pancreatitisLinks with pancreatitis
Pancreas AnatomyPancreas Anatomy
HistologyHistology
DuctDuct
IsletIslet
AcinusAcinusfatfat
PancreatitisPancreatitis
PancreasPancreas - - an organ that makes an organ that makes bicarbonatebicarbonate to nutralize gastric acid, to nutralize gastric acid, enzymesenzymes to digest the contents of a meal and to digest the contents of a meal and insulininsulin to signal the body to to signal the body to store ingested nutrients.store ingested nutrients.
Acute PancreatitisAcute Pancreatitis - An acute, potentially life-threatening condition - An acute, potentially life-threatening condition presenting with severe abdominal pain in which the pancreas appears to presenting with severe abdominal pain in which the pancreas appears to digest itself. It is usually caused by gallstones, alcohol or is idiopathic.digest itself. It is usually caused by gallstones, alcohol or is idiopathic.
Chronic Pancreatitis Chronic Pancreatitis - an irreversible scarring of the pancreas with - an irreversible scarring of the pancreas with permanent loss of pancreatic function that typically causes unrelenting permanent loss of pancreatic function that typically causes unrelenting abdominal pain.abdominal pain.
Hereditary Pancreatitis Hereditary Pancreatitis - - a unusual form of acute and chronic pancreatitis that a unusual form of acute and chronic pancreatitis that runs in families. The risk of pancreatic cancer is >50 times normal.runs in families. The risk of pancreatic cancer is >50 times normal.
PanPancreacreass
CT of Pancreatic NecrosisCT of Pancreatic Necrosis
CT of Severe Chronic PancreatitisCT of Severe Chronic Pancreatitis
Chronic Pancreatitis: 1995Chronic Pancreatitis: 1995
“chronic pancreatitis remains an enigmatic process of uncertain pathogenesis, unpredictable clinical course, and unclear treatment”
Medical Progress: Chronic Pancreatitis. Volume 332(22) 1 Jun 1995 pp 1482-1490
Michael L Steer, Irving Waxman, Steven Freedman
Origins of Pancreatitis Origins of Pancreatitis
Pre-1896Pre-1896:: Pancreatitis is an infectionPancreatitis is an infection
1896:1896: Pancreatitis is pancreas autodigestionPancreatitis is pancreas autodigestion 1996:1996: Hereditary Pancreatitis is caused by Hereditary Pancreatitis is caused by
mutations in the mutations in the cationic cationic trypsinogentrypsinogen gene (PRSS1)gene (PRSS1)
Hereditary PancreatitisHereditary Pancreatitis
Hereditary pancreatitis Hereditary pancreatitis (HP) is an unusual form (HP) is an unusual form of acute and chronic pancreatitis that runs in of acute and chronic pancreatitis that runs in families. The risk of pancreatic cancer is >50 families. The risk of pancreatic cancer is >50 times normal.times normal.
Although HP is only responsible for 2-3% of all Although HP is only responsible for 2-3% of all cases of chronic pancreatitis, study of this disease cases of chronic pancreatitis, study of this disease has revolutionized our understanding of has revolutionized our understanding of pancreatic diseasespancreatic diseases
PaPancrencreasas
E-mailE-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
HP Kindred without 7q35 linkage HP Kindred without 7q35 linkage
A large family was identified through self-referralA large family was identified through self-referral
Seventy-one membersSeventy-one membersSix affectedSix affectedTwo obligate carriersTwo obligate carriers
Linkage of HP to Chromosome 7q35Linkage of HP to Chromosome 7q35
D7S
505
D7S
661
D7S
684
D7S
523
D7S
461
D7S
495
D7S
483
D7S
550
D7S
559-5
3
0
LO
D S
core
s
HP GENE
5
Whitcomb et al. GASTROENTEROLOGY 110:1975, 1996Whitcomb et al. GASTROENTEROLOGY 110:1975, 1996
0.00001
0.001
0.1
(P v
alu
e)
0.01
0.00014
21
Markers on chromosome 7
HereditaryHereditaryPancreatitis Pancreatitis
GeneGene
Cystic Cystic FibrosisFibrosisGeneGene
Chromosome 7
TCRBTCRB
Discovery of the Pancreatitis GeneDiscovery of the Pancreatitis Gene
DNA
1. Family 2. Genetic Mapping
Chromosome 7
HereditaryPancreatitisgene
ccaccaccagtcaggcacactctaccaccATGAATCCACTCCTGATCCTTACCTTTGT
GG/ACAGCTGC TCgtgagtatcatgccctgcctcaggccccaaccacccccccgttcctggccga
3. Mutation
Mutation in the trypsinogenDNA sequenceRecruitment
4. Mechanism
Functional significancedetermined
Trypsinogen
Whitcomb et al 1996
Physiology of TrypsinPhysiology of Trypsin
EnterokinaseEnterokinase
TrypsinogenTrypsinogen
ChymotrypsinogenChymotrypsinogen
ProelastaseProelastase
ProcarboxypeptidaseProcarboxypeptidase
ProenzymesProenzymes
TrypsinTrypsin
ChymotrypsinChymotrypsin
ElastaseElastase
CarboxypeptidaseCarboxypeptidase
EnzymesEnzymes
TrypsinTrypsin
ChymotrypsinChymotrypsin
ElastaseElastase
CarboxypeptidaseCarboxypeptidase
EnzymesEnzymes
TRYPSIN Solid Food
Fail-safe Trypsin InactivationFail-safe Trypsin Inactivation
Trypsinogen
Trypsin (wt)Trypsin (wt)
+
-
(Autoactivation)
Proenzymes Enzymes
Whitcomb et al, Whitcomb et al, Nature Genetics Nature Genetics 19961996
-
-
TrypsinTrypsinTrypsinTrypsin
Trypsin
-
-
PSTIPSTI
AutodigestionAutodigestionPancreatitisPancreatitis
R122R122 TrypsinTrypsinTrypsinTrypsinH122
??
PSTIPSTI
Trypsinogen Alignment & MutationsTrypsinogen Alignment & Mutations
Exon 1 signal peptideCODON 1 10 14
| | |CT MNPLLILTFVAAALAT MNLLLILTFVAAAVMT MNPFLILAFVGAAVChy MAFLWLLSCWALLGTTF
Exon 2 TAP
CODON 15 16 23 29 40 50 60 67 | | | | | | | |CT A APFDDDDK IVGGYNCEENSVPYQVSLN SGYHFCGGSLINEQWVVSAGHCYKSAT A APFDDDDK IVGGYICEENSVPYQVSLN SGYHFCGGSLISEQWVVSAGHCYKSMT A VPFDDDDK IVGGYTCEENSLPYQVSLN SGSHFCGGSLISEQWVVSAAHCYKTChy G CGVPAIHPVLSGLSR IVNGEDAVPGSWPWQVSLQDKTGFHFCGGSLISEDWVVTAAHCGVR
| | || | | | | Chy# 1 10 2021 30 40 50 57
Exon 3 CODON 68 70 80 90 100 110 120 122 130 140 150 152 | | | | | | | | | | | |CT RIQ VRLGEHNIEVLEGNEQFINAAKIIRHPQYDRKTLNNDIMLIKLSSRAVINARVSTISLPT APPA TGTKCLISGWGNTASSGAAT RIQ VRLGEHNIEVLEGNEQFINAAKIIRHPKYNSRTLDNDILLIKLSSPAVINSRVSAISLPT APPA AGTESLISGWGNTLSSGAMT RIQ VRLGEHNIKVLEGNEQFINAAKIIRHPKYNRDTLDNDIMLIKLSSPAVINARVSTISLPT APPA AGTECLISGWGNTLSFGAChy TSDVVVAGEFDQGSDEENIQVLKIAKVFKNPKFSILTVNNDITLLKLATPARFSQTVSAVCLPSADDDFPAGTLCATTGWGKTKYNAN | | | | | | | | | | |
Chy# 62 70 80 90 100102 110 117 120 130 140
APFDDDDK IVGGYNCEENSVPYQVSLN
Whitcomb MCNA 2000
Whitcomb 1996Whitcomb 1996
Gorry 1997Gorry 1997Ferec 1999Ferec 1999Witt 1999Witt 1999 Teich 2000Teich 2000
PfutzetPfutzet 1999 1999 (+CFTR R117H) (+CFTR R117H)
PRSS1 Mutations - OverviewPRSS1 Mutations - Overview
Two mutations are both common and disease-causing: Two mutations are both common and disease-causing: PRSS1 R122H and N29I (new numbers) PRSS1 R122H and N29I (new numbers)
Individuals with either of the two mutations have Individuals with either of the two mutations have about an 80% chance of developing acute pancreatitis.about an 80% chance of developing acute pancreatitis.
Of those with acute pancreatitis, about half develop Of those with acute pancreatitis, about half develop chronic pancreatitischronic pancreatitis
40% with chronic pancreatitis will develop pancreatic 40% with chronic pancreatitis will develop pancreatic cancer by age 70 (smoking doubles risk)cancer by age 70 (smoking doubles risk)
SPINK1/PSTI Alignment & MutationsSPINK1/PSTI Alignment & Mutations
Exon 1 Exon 2Codon # 1 10 18 24 29 obs var | | P | | | human MKVTGIFLLSALALLSLS * GNTGADSLGRE *Porcine TSPQRE rat MKVAIIFLLSALALLNLA GNTTAKVIGKK
| | Peptide # 1 6
Exon 3Codon # 30 34 40 50 55 60 65 obs var | S |* E S | |human AKCYNELNGCTKIYDPVCGTDGNTYPNECVLCFENR * *porcine ATCTSEVSGCPKIYNPVCGTDGITYSNECVLCSENKrat ANCPNTLIGCPRDYDPVCGTDGKTYANECILCFENR
| | | | | |Peptide # 7 11 20 30 40 42
Exon 4Codon # 66 70 79 obs var | | |human KRQTSILIQKSGPCporcine KRQTPVLIQKSGPCrat KFGTSIRIQRRGLC
| | |Peptide # 43 50 56
Pfutzer et al, Gastroenterology, 2000Pfutzer et al, Gastroenterology, 2000
Comparison of Comparison of human , porcinehuman , porcine andand rat rat , SPINK1/PSTI. , SPINK1/PSTI. Obs var;Obs var; observed variations in human observed variations in human protein sequence deduced from protein sequence deduced from allele polymorphisms. allele polymorphisms.
*;*; the “bait” lysine (K) in human the “bait” lysine (K) in human and porcine, and arginine (R ) in and porcine, and arginine (R ) in rat that projects into the rat that projects into the specificity pocket of trypsin specificity pocket of trypsin during trypsin inhibition. during trypsin inhibition.
Homology between human and Homology between human and porcine SPINK1 (PSTI) is 71%porcine SPINK1 (PSTI) is 71%
Changes human Changes human to porcineto porcine
SPINK1 / PSTI N34S MutationSPINK1 / PSTI N34S Mutation
Superposition of the Superposition of the porcineporcine SPINK1 SPINK1 structure (blue) on structure (blue) on the the humanhuman (modified (modified for chymotrypsin for chymotrypsin specificity) SPINK1 specificity) SPINK1 structure (red). structure (red).
Model by Andrew Brunskil Model by Andrew Brunskil & William F. Furey & William F. Furey
Pfutzer et al, Gastroenterology, 2000Pfutzer et al, Gastroenterology, 2000
SPINK1 Genotype-PhenotypeSPINK1 Genotype-Phenotype
656055504540353025201510500
10
20
30
40
50
60
70
80
90
100
SPINK1 N34S
Cumulative Incidence of PancreatitisCumulative Incidence of Pancreatitis
Age of Symptom Onset (years)Age of Symptom Onset (years)
AffectedAffected(% total)(% total)
SPINK1 N34S / N34SICP
SPINK1 N34S / P55S
Pfutzer et al, Gastroenterology, 2000Pfutzer et al, Gastroenterology, 2000
SPINK1 Mutations - OverviewSPINK1 Mutations - Overview
SPINK1/PSTI mutations are common in the population (~2%)SPINK1/PSTI mutations are common in the population (~2%) SPINK1/PSTI are clearly associated with ICP (~25%). SPINK1/PSTI are clearly associated with ICP (~25%). The mutation associated risk is low (<1%). The mutation associated risk is low (<1%). Modeling and familial clustering suggest that SPINK1 Modeling and familial clustering suggest that SPINK1
mutations are disease modifying.mutations are disease modifying. SPINK1/PSTI mutations may lower the threshold for SPINK1/PSTI mutations may lower the threshold for
pancreatitis from other genetic or environmental factors, but pancreatitis from other genetic or environmental factors, but by themselves are not disease causingby themselves are not disease causing
The N34S mutations has a world-wide distribution.The N34S mutations has a world-wide distribution.
SPINK1 Mutations - OverviewSPINK1 Mutations - Overview
SPINK1/PSTI mutations are common in the population SPINK1/PSTI mutations are common in the population (~2%)(~2%)
SPINK1/PSTI are clearly associated with ICP (~25%). SPINK1/PSTI are clearly associated with ICP (~25%). The mutation associated risk is low (<1%). The mutation associated risk is low (<1%). Modeling and familial clustering suggest that SPINK1 Modeling and familial clustering suggest that SPINK1
mutations are disease modifying.mutations are disease modifying. SPINK1/PSTI mutations may lower the threshold for SPINK1/PSTI mutations may lower the threshold for
pancreatitis from other genetic or environmental factors, pancreatitis from other genetic or environmental factors, but by themselves are not disease causingbut by themselves are not disease causing
Smoking & Risk of Cancer in HPSmoking & Risk of Cancer in HP
8080707060605050404030302020101000
EverEverSmokedSmoked
Never Never SmokedSmoked
Age at diagnosis ofAge at diagnosis of pancreatic cancerpancreatic cancer
GPGP HP HP HP + HP + Smoked Smoked
150150
100100
5050
00
Rel
ativ
e R
isk
Rel
ativ
e R
isk
Age
(ye
ars)
Age
(ye
ars)
Risk of Pancreatic CancerRisk of Pancreatic Cancer
A.B. Lowenfels, P. Maisonneuve, D. C.Whitcomb, and A.B. Lowenfels, P. Maisonneuve, D. C.Whitcomb, and the International Hereditary Pancreatitis Study Groupthe International Hereditary Pancreatitis Study Group