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Genetics of Pancreatic Cancer
Gloria M. Petersen, Ph.D.
Mayo Clinic
Rochester, Minnesota
Pancreatic Cancer Action Network – Chicago Symposium
Genetics of Pancreatic Cancer
 Why we study families with
pancreatic cancer
 What are genes and DNA?
 New discoveries in genetics of
pancreatic cancer
Pancreatic Cancer: Risk Factors

Age

Diabetes

Race

Chronic Pancreatitis

Smoking

Family history

Obesity

Genes /Shared environment
10% of pancreatic cancer patients have a
first degree relative with pancreatic cancer
Studies show that
the risk for a
parent, sibling or
child of a pancreatic
cancer patient to
also develop this
cancer is 2 to 5
times higher than
the risk in the
general population.
Positive
Family History
Three-Generation Family Tree
German/Polish
2
d. 70
English/Irish
2
Pancreas Ca, dx 65
2
2
d. 80
d. 85
2
1
1
2
2
2
Pancreas Ca, dx 62
67
65
55
Diabetes, dx 45
52
59
3
Pancreas Ca, dx 54
1
35
30
1. First degree relatives
2. Second degree
3. Third degree
Familial Pancreatic Cancer
Mayo 627
Dx 79
NS
Dx 58
S
Dx 79
NS
Dx 58
NS
Dx unk
NS
Dx 87
Working definition:
Dx 57
Families in which
at least two first degree NS
relatives
have
= Nonsmoker
S
S = Smoker
been diagnosed with pancreatic cancer.
Hruban and Petersen, 1997
Family History is one way to:
 Identify who is at
risk
 Refer for genetic
risk counseling
 Recommend who
needs checkups more
often
Genetics of Pancreatic Cancer
 Why we study families with
pancreatic cancer
 What are genes and DNA?
 New discoveries in genetics of
pancreatic cancer
Every human being is genetically unique.
46 Human Chromosomes
p
Centromere
q
(Chromosome 5)
Chromosomes, DNA, and Genes
Gene
Cell
Nucleus
Chromosomes
Protein
Adenine (A)
Cytosine (C)
Thymine (T)
Guanine (G)
How do geneticists study cancer?
?
NORMAL
CANCER
DNA
Sequencing
Genetics of Pancreatic Cancer
 Why we study families with
pancreatic cancer
 What are genes and DNA?
 New discoveries in genetics of
pancreatic cancer
Hereditary Disorders and Genes Associated
with Pancreas Cancer
Disorder
Hereditary Pancreatitis
Gene
PRSS1 (Cationic trypsinogen)
Familial Atypical Multiple Mole
Melanoma Syndrome (FAMMM)
P16 (CDKN2A)
BRCA2
BRCA2
Hereditary Colorectal Cancers
APC, MSH2, MLH1
Peutz-Jeghers Syndrome
STK11/LKB1
Fanconi Anemia genes
FANCC, FANCG
Family history of some cancers is associated
with younger age of onset of pc
Breast Cancer
Melanoma
Ovarian Cancer
McWilliams RR et al. Clin
Gastro Hepatol 4:1143, 2006
McWilliams R et al. Gut 54:1661, 2005
Cystic Fibrosis Gene (CFTR) and
Younger Onset Pancreatic Cancer
 Cystic fibrosis (CF) is a hereditary disorder
 CF is caused by dysfunction of cellular
membrane and regulation of ions
 Altered CFTR protein impairs glandular
secretion
 Result is chronic lung disease, pancreatic
insufficiency
McWilliams R et al. Gut 54:1661, 2005; Cancer 116: 203-9, 2010
CFTR Mutations Associated with Younger Onset PC
CFTR Mutation Carrier Rates
9.00
8.4
8.00
7.00
Percent
Percent
6.00
5.00
4.1
OR 2.2 (95% CI 1.2-3.3)
P=0.006
• 2010 update: Results remain
significant (OR=1.82) with larger
number (~950) tested; OR=1.4
all ages
Percent CFTR
Mutation Carriers
• Sequencing suggests 16% of
patients have two different
mutations on both chromosomes
4.00
3.00
2.00
1.00
0.00
Young Onset PC
Under age 60
N=166
Control Group
N=5,349
12
1
1
ΔF508
R117H
N1303K
Is There A Genetic Connection Between
Melanoma and Pancreatic Cancer?
• Methods:
• 1,537 pancreatic adenocarcinoma patients
• Mutation analysis of CDKN2A gene
• Results:
• 9 (0.6%) carried germline mutations in CDKN2A
• Carriers were more likely to have:
• Family history of pancreatic cancer
rate 3.3%
(p= 0.003); carrier
• Family history of melanoma (p= 0.03); carrier
• Personal history of melanoma (p= 0.01)
rate 5.3%
McWilliams RR et al. Eur J Hum Genetics, 2011 Apr;19(4):472-8.
Genetic susceptibility to pancreatic cancer
Young onset
(<60) sporadic
~20%
Familial
pancreatic cancer
~10%
?
Sporadic
~85%
Known cancer
genes (~5%)
Associations with DNA Repair Genes
#
Cases
309
384
481
#
Controls
964
357
625
Finding
Site,
Reference
XRCC1 & heavy smoking:  2.4-fold for
Northern
California, Duell
et al. 2002
XRCC1 and APE1:  5-fold
Houston,
Jiao et al. 2006
men;  7-fold for women
XPF/ERCC4:  (0.59)
XPD/ERCC2 & heavy smoking:  2 to 2.8
Minnesota,
McWilliams et
al. 2008
A NER pathway approach (27 genes, 236
SNPs):
MMS19L:  (0.6 to 0.8)
Minnesota,
McWilliams et
al. 2009
fold
1,143
1,097
PanScan – a GWAS

PanScan 1
– Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, et al.
Genome-wide association study identifies variants in the ABO
locus associated with susceptibility to pancreatic cancer. Nature
Genetics 41:986-90, September, 2009.
– 2000 pairs

PanScan 2
– Petersen GM, Amundadottir A, Fuchs CS, et al. A genome-wide
association study identifies pancreatic cancer susceptibility loci
on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nature
Genetics, Feb 2010.
– 3,850 pairs
GWAS Results: ABO Blood Group
All Studies
ABO Blood Groups and Cancer


Gastric Cancer - well established
– Increased risk for blood group A
Pancreatic Cancer -Possibly risk with
ABO
 Risk
Bodmer and Bonilla Nat Gen 2008
Blood Group
A
AB
B
 Risk
1.32
1.51
1.72
JNCI 2009; 101:424-431
Genetic susceptibility is heterogeneous
Genetic polymorphisms and
GxE interactions
Young onset
(<60) sporadic
~20%
?
Familial pancreatic cancer
<10%
Sporadic
~70%
Known genetic syndromes
~3%
How do we find new genes that confer
susceptibility to familial PC?
Pancreatic
Epidemiology
Pancreatic
CancerCancer
Genetic Genetic
Epidemiology
(PACGENE) (PACGENE)
Consortium
Consortium Sites
Funded by NCI grant R01
CA97075
• Prospective accrual of FPC
kindreds
• Whole genome scan
• Linkage analysis
• TGEN
As of February 2011:
• 31,184 screened
• 2,509 with +FHx enrolled
(16,297 mbrs)
• 8,316 family enrolled
• Mayo Clinic
• Mt. Sinai /Toronto
•Karmanos CI
• Creighton Univ
• Dana Farber
•Johns Hopkins
•MD Anderson CC
5.5 million
genotypes
tested!
Petersen GM et al. Cancer Epi Biomarkers Prev, 15:704, 2006
New familial pancreatic cancer gene: PALB2
• 96 FPC patients screened for PALB2 mutations (90 Caucasian)
• Average onset age: 66.7 years (in non PALB2 kindreds, 65.3)
• Previous published study: no mutations in 1,084 normal controls.
Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identifies
PALB2 as a pancreatic cancer susceptibility gene. Science, 324:217, 2009.
Where are genes for inherited pancreatic cancer?
PRSS1
BRCA2
P16, PALB2
Others:
•FANCC (9q)
•CFTR (7q)
•PJS (19p)
•MMR (2p, 3p)
•APC (5q)
•PALLD (4q)
At least 3
other genomic
regions
involved
Genetic susceptibility to pancreatic cancer
Genetic polymorphisms
and GxE interactions
(DNA Repair, ABO, CLPTM1L-TERT, NR5A)
Young onset
(<60) sporadic
~20%
?
Sporadic
~70%
CFTR
Familial pancreatic cancer
<10%
BRCA2, p16, PALB2, etc.
Known genetic syndromes
~3%
Hereditary pancreatitis, FAMMM, etc.
Conclusions

Research has shown that there are
individuals at increased risk for developing
pancreatic cancer

Genetic susceptibility is heterogeneous

Limited genetic testing is available

Our work continues to better understand
the genetics and to help patients
Collaborators & Acknowledgments
Mayo Clinic
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Rob McWilliams, MD
Mariza de Andrade, Ph.D.
Kari Rabe, M.S.
Bill Bamlet, M.S.
Suresh Chari, M.D.
Wilma Lingle, Ph.D.
Fergus Couch, Ph.D.
Ed Highsmith, M.D.
Julie Cunningham, Ph.D.
Thomas Smyrk, M.D.
Hugues Sicotte, Ph.D.
Traci Hammer, Cindy Chan, Jodie
Cogswell, Bridget Eversman
• RO1 CA97075
• SPORE (P50 CA 102701)
• Pancreatic Cancer Action Network
Johns Hopkins University
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Ralph Hruban, M.D.
Mike Goggins, M.D.
Alison Klein, Ph.D.
Mimi Canto, M.D.
PACGENE collaborators
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Melissa Bondy, Ph.D. – MDA
Steve Gallinger, M.D. – U Toronto
Ann Schwartz, Ph.D. - Wayne SU
Sapna Syngal, M.D. – DFCI
Kevin Brown, Ph.D. - TGEN
Daniela Seminara, Ph.D. – NCI
Henry Lynch, M.D. – Creighton U
Ctr for Inherited Disease Research
David Hogg, Ph.D.
PanScan Collaborators - NCI
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Patricia Hartge, Ph.D.
Robert Hoover, Ph.D.
Stephen Chanock, Ph.D.
Laufey Amundadottir, Ph.D.