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Relative Risks for Cancers in the Neurofibromatosis ...

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Relative Risks for Cancers in the Neurofibromatosis ... Presentation Transcript

  • 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
      • 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 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
    • 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. 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. 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 Records 100,000+ NCI SEER registry records
    • Hospital 1 million+ individuals, diagnosis, procedures,
    • medications, treatment response, …
    • Driver’s License Body Mass Index
    • Birth Certificates birth weight, APGAR, gestational diabetes, …
    • Other longevity, 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 #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. 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