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Relative Risks for Cancers in the
Neurofibromatosis Population in Utah
David Viskochil
Lisa Cannon-Albright
David Stevenso...
NF1: A familial cancer syndrome
• Sarcoma
– Malignant Peripheral Nerve Sheath Tumor (MPNST) 10% lifetime risk
– Rhabdomyos...
Ras-associated cancers
• Activating RAS mutations leading to loss of GTP
hydrolysis is detected in ~30% of all human
cance...
NF1 and cancer risk: lit. review
• Epidemiological
– Blatt J et al, 1986, Neurofibromatosis and Childhood tumors. Cancer
5...
L Ding et al. Nature 455, 1069-1075 (2008) doi:10.1038/nature07423
Significantly mutated pathways in lung adenocarcinomas.
The Cancer Genome Atlas Research Network Nature 000, 1-8 (2008) doi:10.1038/nature07385
Frequent genetic alterations in 3 ...
Relative Risk of cancers in NF1: UK
Using the Utah Population Database in Utah
we propose to verify these results for vari...
Relative risk of cancer in NF1
• Objectives of study:
– Identify cancers in excess in NF1 compared to
the unaffected popul...
Relative risk of cancer in NF1 Study
• Aims:
– Identify high-risk NF1 pedigrees in the UPDB
– Screen the University of Uta...
Original Utah Genealogy Data
• LDS make up 75% of the state of Utah
– family historians trace their ancestries as far as p...
Original Utah Population DataBase
Phenotype Data
Death Certificates 250,000+ death certificates
from 1970 -
coded with ICD...
UPDB Phenotype Data Today
Death Certificates 600,000+ death certificates
back to 1904
Cancer Records 100,000+ NCI SEER reg...
Clinical Encounters in UPDB
Link between the University of Utah Health Sciences Center
(UUHSC) Enterprise Data Resource Ce...
Relative Risks for Cancers in NF1
• Identified 245 cases of NF1 (1-94 years)
• Observed 31 cases of cancer
• Expected 3.23...
Cancers in Excess in NF
Population of Utah
Site #Obs Exp RR 95% CI
Brain 11 0.15 72.23 40.51, 119.55
Ewings Sarcoma * 52.2...
CNS tumors in Utah NF1 Population
237.7 (von Recklinghausen; 67): 2 astrocytomas
2 glioblastomas
1 meningioma*
237.70 (NF,...
CTOS 2009, Miami
Cluster with 3 affected
NF1 patients
Attempt to identify these
Individuals in the NF
Clinic Registry.
Eva...
Identification of High-Risk NF1 Pedigrees
Clusters:
– Single cases without other relatives with NF1
– 2 affected relatives...
Future studies
• UPDB invites patients identified by this
analysis to enroll in additional studies:
– review medical recor...
Thank you –
Yes there is snow
see you this winter!
Acknowledgements:
Huntsman Cancer Institute
Grant from Cancer Control a...
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Relative Risks for Cancers in the Neurofibromatosis ...

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Relative Risks for Cancers in the Neurofibromatosis ...

  1. 1. Relative Risks for Cancers in the Neurofibromatosis Population in Utah David Viskochil Lisa Cannon-Albright David Stevenson University of Utah CTOS 2009, Miami
  2. 2. NF1: A familial cancer syndrome • Sarcoma – Malignant Peripheral Nerve Sheath Tumor (MPNST) 10% lifetime risk – Rhabdomyosarcoma rare – Angiosarcoma rare • Plexiform neurofibroma (benign) common – 20-25% • Gastrointestinal stromal tumor (WT GIST) rare • Pheochromocytoma rare • Astrocytoma – High-grade Astrocytoma (glioblastoma) rare – Optic nerve pathway tumor (low-grade) common - ~15% • JMML (jeuvenile myelomonocytic leukemia) rare NF1 gene product (neurofibromin) is a negative regulator of Ras. NF1 P P P P Activated RTK Growth factor GDP GDP GDP GTP Grb2 Sos1 Signal Ras GTPase activity Ras GTP Ras Ras NF1 GAP activity NF1 is an autosomal dominant condition that affects ~1/3000 worldwide. Double inactivation of NF1 is associated with NF1-related tumors.
  3. 3. 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% [pancreas, lung, colon] – NRAS in ~15% [melanoma, liver, myeloid] – HRAS in ~ 1% [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
  4. 4. NF1 and cancer risk: lit. review • 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- • 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- • 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-
  5. 5. L Ding et al. Nature 455, 1069-1075 (2008) doi:10.1038/nature07423 Significantly mutated pathways in lung adenocarcinomas.
  6. 6. The Cancer Genome Atlas Research Network Nature 000, 1-8 (2008) doi:10.1038/nature07385 Frequent genetic alterations in 3 critical signalling pathways in human glioblastoma.
  7. 7. Relative Risk of cancers in NF1: UK Using the Utah Population Database in Utah we propose to verify these results for various cancers in the NF1 population. 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. • 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 Walker et al., 2006, Br J Can
  8. 8. 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.
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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
  13. 13. 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
  14. 14. Relative Risks for Cancers in NF1 • 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) Clinical encounters matched to individuals in the Utah Cancer Registry and the Utah Population Database
  15. 15. Cancers in Excess in NF Population of Utah Site #Obs Exp RR 95% CI Brain 11 0.15 72.23 40.51, 119.55 Ewings Sarcoma * 52.22 2.69, 247.72 Small Intestine * 86.17 4.43, 408.77 Spinal Cord * 93.14 16.55, 293.20 Tongue * 75.02 3.86, 355.87 MPNST 5 * Small number of observed cases (<5; at risk for loss of confidentiality)
  16. 16. 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.
  17. 17. CTOS 2009, Miami Cluster with 3 affected NF1 patients Attempt to identify these Individuals in the NF Clinic Registry. Evaluate cancer phenotype in connecting individuals
  18. 18. Identification of High-Risk NF1 Pedigrees Clusters: – 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)
  19. 19. 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
  20. 20. 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

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