Relative Risks for Cancers in the Neurofibromatosis Population in Utah

David ViskochilLisa Cannon-Albright

David Stevenson

University of Utah

CTOS 2009, Miami

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 anegative regulator of Ras.

NF1

P

P

P

P

Activated RTK

Growth factor

GDP

GDP

GDP

GTP

Grb2 Sos1

Signal

Ras GTPaseactivity

Ras

GTP

Ras

Ras

NF1 GAP activity

NF1 is an autosomal dominant conditionthat affects ~1/3000 worldwide.

Double inactivation of NF1 is associatedwith NF1-related tumors.

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

• 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-

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 critical signalling pathways in human glioblastoma.

Relative Risk of cancers in NF1: UK

Using the Utah Population Database in Utahwe propose to verify these results for variouscancers 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

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-0age, 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 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

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

• 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 Registryand the Utah Population Database

Cancers in Excess in NF Population of Utah

Site #Obs Exp RR 95% CIBrain 11 0.15 72.23 40.51, 119.55Ewings Sarcoma * 52.22 2.69, 247.72Small Intestine * 86.17 4.43, 408.77Spinal Cord * 93.14 16.55, 293.20Tongue * 75.02 3.86, 355.87

MPNST 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 astrocytomas2 glioblastomas1 meningioma*

237.70 (NF, Unspecified; 100): 3 astrocytomas

237.71 (Neurofibromatosis 1; 78): 3 pilocytic astrocytomas1 glioma, malignant1 cranial nerve cancer

High-grade astrocytomas (glioblastoma) are as concerningas MPNST in the NF1 population.

CTOS 2009, Miami

Cluster with 3 affected NF1 patients

Attempt to identify theseIndividuals in the NFClinic Registry.

Evaluate cancer phenotypein connecting individuals

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)

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 snowsee you this winter!

Acknowledgements:Huntsman Cancer InstituteGrant from Cancer Control and Population Sciences, HCIUtah Cancer Registry (NCI/SEER)Utah Population Database