Transcript Relative Risks for Cancers in the Neurofibromatosis Population in

Relative Risks for Cancers in the
Neurofibromatosis Population in Utah
David Viskochil
Lisa Cannon-Albright
David Stevenson
University of Utah
CTOS 2009, Miami
NF1: A familial cancer syndrome
NF1 is an autosomal dominant condition
that affects ~1/3000 worldwide.
Ras GTPase
activity
Growth
factor
Ras
Ras
GTP
GDP
Ras
GDP
P
Double inactivation of NF1 is associated
with NF1-related tumors.
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GTP
P Grb2
Sos1
Signal
NF1 gene product (neurofibromin) is a
negative regulator of Ras.
P
NF1 GAP
activity
P
Activated
RTK
Sarcoma
– Malignant Peripheral Nerve Sheath Tumor (MPNST)
– Rhabdomyosarcoma
– Angiosarcoma
Plexiform neurofibroma (benign)
Gastrointestinal stromal tumor (WT GIST)
Pheochromocytoma
Astrocytoma
– High-grade Astrocytoma (glioblastoma)
– Optic nerve pathway tumor (low-grade)
JMML (jeuvenile myelomonocytic leukemia)
GDP
NF1
10% lifetime risk
rare
rare
common – 20-25%
rare
rare
rare
common - ~15%
rare
Ras-associated cancers
• Activating RAS mutations leading to loss of GTP
hydrolysis is detected in ~30% of all human
cancers. Of those with mutant RAS:
– KRAS in 85%
– NRAS in ~15%
– HRAS in ~ 1%
[pancreas, lung, colon]
[melanoma, liver, myeloid]
[bladder cancer]
• NF1 and RASA1 are Ras-GAPs for WT Ras
• NF1 and RASA1 inactivation does not overlap
with activating RAS mutations in most cancers
NF1 and cancer risk: lit. review
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Epidemiological
– Blatt J et al, 1986, Neurofibromatosis and Childhood tumors. Cancer
57:1225– Sorensen S et al, 1986, Long-term follow-up of von Recklinghausen NF.
Survival and malignant neoplasms. N Engl J Med 314:1010– Matsui I et al, 1993, NF1 and Childhood Cancer. Cancer 72:2746– Rasmussen S et al. 2001. Mortality in NF1: An analysis using US death
certificates. Am J Hum Genetics 68:1110– Walker L et al. 2006. A prospective study of NF1 cancer incidence in the UK.
Br J Cancer 95:233– Sharif S et al. 2007. Women with NF1 are at a moderately increased risk of
developing breast cancer and should be considered for early screening. J
Med Genetics 44:481-
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Targeted Cancers – limited by low sensitivity of NF1 mutation detection
– Sangha et al, 2008, NF1 defects are common in human ovarian serous
carcinomas and co-occur with TP53 mutations. Neoplasia 10:1362-
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Genome Profiling – unselected associations
– Ding L, Getz G, Wheeler D et al, 2008, Somatic mutations affect key
pathways in lung adenocarcinoma. Nature 455:1069– Cancer Genome Atlas Research Network, 2008, Comprehensive genomic
characterization defines human glioblastoma genes and core pathways.
Nature 455:1061-
Significantly mutated pathways in lung adenocarcinomas.
L Ding et al. Nature 455, 1069-1075 (2008) doi:10.1038/nature07423
Frequent genetic alterations in 3 critical signalling pathways in human glioblastoma.
The Cancer Genome Atlas Research Network Nature 000, 1-8 (2008) doi:10.1038/nature07385
Relative Risk of cancers in NF1: UK
UK Study: UK NF1 Association cross-referenced with the UK Cancer Registry
Overall risk of cancer was 2.7 times higher than in the general population.
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Connective tissue SIR=122 (95% CI 7.8-24%)
Brain
SIR=22.6 (95% CI 3.9-16%)
Breast
SIR=1.87 (95% CI 0.61-4.37)*
No statistically significant excess of cancers at
other sites
Using the Utah Population Database in Utah
we propose to verify these results for various
cancers in the NF1 population.
Walker et al., 2006, Br J Can
Relative risk of cancer in NF1
• Objectives of study:
– Identify cancers in excess in NF1 compared to
the unaffected population in Utah
– Identify clusters of NF1 patients and determine
if each distant relative harbors the same NF1
gene haplotype.
Relative risk of cancer in NF1 Study
• Aims:
– Identify high-risk NF1 pedigrees in the UPDB
– Screen the University of Utah Health Sciences Center
hospital and clinics (warehouse data) for ICD-9
diagnostic codes for NF1 patients
• 237.7 - von Recklinghausen disease
• 237.70 – Neurofibromatosis, unspecified
• 237.71- Neurofibromatosis type 1
– Score for 40 types of cancer from the Utah Cancer
Registry to determine relative risk for NF1 patients
compared to the Utah population
CCPS; HCI
Original Utah Genealogy Data
• LDS make up 75% of the state of Utah
– family historians trace their ancestries as far as possible
– records collected in the Family History Library of the Church
• The Utah Genealogy Database used 3-generation family
genealogy sheets submitted by members of the Church of Jesus
Christ of Latter-day Saints
• Skolnick selected sheets containing at least one life event in
Utah or on the pioneer trail (1840-1850); record linking
accomplished during data entry
• Original Utah genealogy included 1.6 million individuals linked in
genealogies 6 - 7 generations deep
Courtesy Lisa Cannon-Albright
Original Utah Population DataBase
Phenotype Data
Death Certificates
250,000+ death certificates
from 1970 coded with ICD
Cancer Records
60,000+ NCI SEER registry records
from 1966 coded with ICD-0
age, stage, grade, survival
100% Utah ascertainment
> 95% follow-up
Courtesy Lisa Cannon-Albright
UPDB Phenotype Data Today
Death Certificates
600,000+ death certificates
back to 1904
Cancer Records
100,000+ NCI SEER registry records
Hospital
1 million+ individuals, diagnosis, procedures,
medications, treatment response, …
Driver’s LicenseBody Mass Index
Birth Certificates
birth weight, APGAR, gestational diabetes, …
Other
longevity, fertility, offspring sex ratio
Courtesy Lisa Cannon-Albright
Clinical Encounters in UPDB
Link between the University of Utah Health Sciences Center
(UUHSC) Enterprise Data Resource Center and UPDB
UUHSC Data Resource Center contains over 1.4 million patient
demographic records
Over 1 million (70%) have been matched to a “person record” in
UPDB
730,000 (50%) matched to a person with two or more
generations
http://www.hci.utah.edu/groups/ppr/
Courtesy Lisa Cannon-Albright
Relative Risks for Cancers in NF1
Clinical encounters matched to individuals in the Utah Cancer Registry
and the Utah Population Database
• Identified 245 cases of NF1 (1-94 years)
• Observed 31 cases of cancer
• Expected 3.23 cases of cancer in age- and
sex-matched population
• RR for any cancer in NF1: 9.6 (95% CI of 6.96-12.97)
Cancers in Excess in NF
Population of Utah
Site
Brain
Ewings Sarcoma
Small Intestine
Spinal Cord
Tongue
MPNST
#Obs
11
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Exp
0.15
RR
72.23
52.22
86.17
93.14
75.02
95% CI
40.51, 119.55
2.69, 247.72
4.43, 408.77
16.55, 293.20
3.86, 355.87
5
* Small number of observed cases (<5; at risk for loss of confidentiality)
CNS tumors in Utah NF1 Population
237.7 (von Recklinghausen; 67):
2 astrocytomas
2 glioblastomas
1 meningioma*
237.70 (NF, Unspecified; 100):3 astrocytomas
237.71 (Neurofibromatosis 1; 78):
3 pilocytic astrocytomas
1 glioma, malignant
1 cranial nerve cancer
High-grade astrocytomas (glioblastoma) are as concerning
as MPNST in the NF1 population.
Cluster with 3 affected
NF1 patients
Attempt to identify these
Individuals in the NF
Clinic Registry.
Evaluate cancer phenotype
in connecting individuals
CTOS 2009, Miami
Identification of High-Risk NF1 Pedigrees
Clusters:
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Single cases without other relatives with NF1
2 affected relatives in a cluster: 56 clusters
3 affected relatives in a cluster: 26 clusters
4 affected relatives in a cluster: 4 clusters
5 affected relatives in a cluster: 2 clusters
6 affected relatives in a cluster: 4 clusters
9 affected relatives in a cluster: 1 cluster
Checked excess cancer in 825 connecting relatives
who did not have a diagnosis of NF1:
Any cancer: 50 obs; 36.58 exp; RR=1.35 (CI 1.06-1.71)
Brain: 2 obs; 0.65 exp; RR=3.06 (CI 0.54-9.62)
Future studies
• UPDB invites patients identified by this
analysis to enroll in additional studies:
– review medical records
– retrieve pathology specimens
– extend family pedigrees
• UPDB contacts the treating physician who
signs letter inviting patient to contact the
investigator for enrollment in additional
studies.
• Investigators cannot contact families directly
Thank you –
Yes there is snow
see you this winter!
Acknowledgements:
Huntsman Cancer Institute
Grant from Cancer Control and Population Sciences, HCI
Utah Cancer Registry (NCI/SEER)
Utah Population Database