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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. Sarcoma

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Relative Risks for Cancers in the Neurofibromatosis Population in Utah

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relative risks for cancers in the neurofibromatosis population in utah

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: A familial cancer syndrome

NF1 is an autosomal dominant condition

that affects ~1/3000 worldwide.

  • 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.

Double inactivation of NF1 is associated

with NF1-related tumors.

ras associated cancers
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
nf1 and cancer risk lit review
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-

Significantly mutated pathways in lung adenocarcinomas.

L Dinget al.Nature455, 1069-1075 (2008) doi:10.1038/nature07423


Frequent genetic alterations in 3 critical signalling pathways in human glioblastoma.

The Cancer Genome Atlas Research Network Nature000, 1-8 (2008) doi:10.1038/nature07385

relative risk of cancers in nf1 uk
Relative Risk of cancers in NF1: UK

UK Study: UK NF1 Association cross-referenced with the UK Cancer Registry

  • 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

Overall risk of cancer was 2.7 times higher than in the general population.

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
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
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


original utah genealogy data
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
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
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

clinical encounters in updb
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

Courtesy Lisa Cannon-Albright

relative risks for cancers in nf1
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
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


* Small number of observed cases (<5; at risk for loss of confidentiality)

cns tumors in utah nf1 population
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
Identification of High-Risk NF1 Pedigrees


  • 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
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!


Huntsman Cancer Institute

Grant from Cancer Control and Population Sciences, HCI

Utah Cancer Registry (NCI/SEER)

Utah Population Database