Pancreatitis and Pancreatic Cancer - PowerPoint PPT Presentation

About This Presentation
Title:

Pancreatitis and Pancreatic Cancer

Description:

Acute Pancreatitis - An acute, potentially life-threatening condition presenting with severe abdominal pain in which the pancreas appears to digest itself. – PowerPoint PPT presentation

Number of Views:82
Avg rating:3.0/5.0
Slides: 25
Provided by: DavidCWh
Learn more at: https://sites.pitt.edu
Category:

less

Transcript and Presenter's Notes

Title: Pancreatitis and Pancreatic Cancer


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
Pancreatitis
Pancreas
  • 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 gt50 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 gt50
    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 1101975, 1996
0.00001
5
Chromosome 7
0.0001
4
0.001
3
0.01
2
0.1
1
LOD Scores
0
Cystic Fibrosis Gene
(P value)
Hereditary Pancreatitis Gene
HP GENE
-5
D7S661
D7S684
D7S523
D7S461
D7S495
D7S483
D7S550
D7S559
D7S505
TCRB
Markers on chromosome 7
14
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 Procarbox
ypeptidase Proenzymes
Trypsin Chymotrypsin Elastase Carboxypeptidase Enz
ymes
Liquid
16
Fail-safe Trypsin Inactivation
Trypsinogen
-

(Autoactivation)
Trypsin (wt)
R122
Whitcomb et al, Nature Genetics 1996
17
Trypsinogen Alignment Mutations
Whitcomb MCNA 2000
Exon 1 signal peptide CODON 1 10
14 CT MNPLLILTFVAAAL AT MNL
LLILTFVAAAV MT MNPFLILAFVGAAV Chy MAFLWLLSCWALLGTT
F Exon 2 TAP CODON 15 16
23 29 40 50 60
67
CT A APFDDDDK
IVGGYNCEENSVPYQVSLN SGYHFCGGSLINEQWVVSAGHCYKS AT
A APFDDDDK IVGGYICEENSVPYQVSLN
SGYHFCGGSLISEQWVVSAGHCYKS MT A VPFDDDDK
IVGGYTCEENSLPYQVSLN SGSHFCGGSLISEQWVVSAAHCYKT Chy
G CGVPAIHPVLSGLSR IVNGEDAVPGSWPWQVSLQDKTGFHFCGGSL
ISEDWVVTAAHCGVR
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 VRLGEHNIEVLEGNEQFINAAKII
RHPQYDRKTLNNDIMLIKLSSRAVINARVSTISLPT APPA
TGTKCLISGWGNTASSGA AT RIQ VRLGEHNIEVLEGNEQFINAAKII
RHPKYNSRTLDNDILLIKLSSPAVINSRVSAISLPT APPA
AGTESLISGWGNTLSSGA MT RIQ VRLGEHNIKVLEGNEQFINAAKII
RHPKYNRDTLDNDIMLIKLSSPAVINARVSTISLPT APPA
AGTECLISGWGNTLSFGA Chy TSDVVVAGEFDQGSDEENIQVLKIAKV
FKNPKFSILTVNNDITLLKLATPARFSQTVSAVCLPSADDDFPAGTLCAT
TGWGKTKYNAN
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
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 1 Exon 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
human AKCYNELNGCTKIYDPVCGTDGNTYPNECVLCFEN
R porcine ATCTSEVSGCPKIYNPVCGTDGITYSNECVLCSE
NK rat ANCPNTLIGCPRDYDPVCGTDGKTYANECILCFENR
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
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 (lt1).
  • 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 (lt1).
  • 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
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
Write a Comment
User Comments (0)
About PowerShow.com