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. NF1: A familial cancer syndrome Sarcoma –Malignant Peripheral Nerve Sheath Tumor (MPNST)10% lifetime risk –Rhabdomyosarcomarare –Angiosarcomarare Plexiform neurofibroma (benign)common – 20-25% Gastrointestinal stromal tumor (WT GIST)rare Pheochromocytomarare 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 is an autosomal dominant condition that affects ~1/3000 worldwide. Double inactivation of NF1 is associated with NF1-related tumors.

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. 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. L Ding et al. Nature 455, 1069-1075 (2008) doi:10.1038/nature07423 Significantly mutated pathways in lung adenocarcinomas.

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. 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%) BrainSIR=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. 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. 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. 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. 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. UPDB Phenotype Data Today Death Certificates 600,000+ death certificates back to 1904 Cancer Records100,000+ NCI SEER registry records Hospital 1 million+ individuals, diagnosis, procedures, medications, treatment response, … Driver’s LicenseBody Mass Index Birth Certificatesbirth weight, APGAR, gestational diabetes, … Otherlongevity, fertility, offspring sex ratio Courtesy Lisa Cannon-Albright

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. 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. Cancers in Excess in NF Population of Utah Site#ObsExp RR 95% CI Brain 11 0.1572.2340.51, 119.55 Ewings Sarcoma *52.222.69, 247.72 Small Intestine *86.174.43, 408.77 Spinal Cord *93.1416.55, 293.20 Tongue *75.023.86, 355.87 MPNST 5 * Small number of observed cases (<5; at risk for loss of confidentiality)

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. 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. 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. 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. 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