RECURRENT CHROMOSOMAL COPY NUMBER ALTERATIONS IN CHORDOMA G. Petur Nielsen; John Iafrate; Zhenfeng Duan; Ramnik Xavier; Joseph Schwab; Andrew Rosenberg;

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Presentation transcript:

RECURRENT CHROMOSOMAL COPY NUMBER ALTERATIONS IN CHORDOMA G. Petur Nielsen; John Iafrate; Zhenfeng Duan; Ramnik Xavier; Joseph Schwab; Andrew Rosenberg; Julie Miller; Edwin Choy; David Harmon; Thomas DeLaney; Vajiya Ramesh; Vikram Deshpande; Francis Hornicek MGH Chordoma Research Group DF/Harvard Cancer Center

D efi nition Malignant tumor with a phenotype that recapitulates the notochord and usually arises within the bones of the axial skeleton.

Incidence – per million –300 cases/yr in US Gender – M:F 1:1 in skull base and 2:1 in spine and sacrum Age – mean 5 th -6 th decade

Symptoms – depend on location Skull – diplopia, headaches, cranial nerve palsies Spine – pain, nerve compression Sacrum – pain, constipation, incontinence, bladder dysfunction

Treatment Surgical resection - primary Radiation therapy - adjuvant Local recurrence - problem

Prognosis Median survival – 6.29 years 5 yr survival-68% 10 yr survival-40% –Alive with local recurrence Survival

What is known? Little to no data concerning the presence of somatic mutations in chordoma Handful of studies have looked at karyotype or Comparative Genomic Hybridization (CGH) No correlations with anatomic site or outcome

Clinical Characteristics of 21 Patients with Chordoma FeatureDetailed featurePatients GenderMale, n (%)15 (71) Female, n (%)6 (29) AgeMedian age, yr (range)63 (46-83) Location of the tumorSkull base, n (%)2 (10) Sacrum, n (%)12 (57) Mobile spine, n (%)7 (33)

Results Average time to death: 8.2 years Local Recurrence: 14 patients Average patient follow-up: 6.1 years

Red= loss in patient. Yellow shading Yellow shading= normal. Green= gain in patient Reference DNAChordoma DNA Array-CGH detection of chromosomal abnormalities  Agilent 244,000 spot oligonucleotide DNA array  Frozen tissue from the 21 chordomas: H&E slides reviewed  Genomic DNA extracted using Gentra Puregene isolation kit  1 microgram of tumor DNA labeled with CY5  1 microgram of normal DNA labeled with CY3  2 day array competitive hybridization  Chromosome plots are log2 ratios of normalized CY5:CY3 signals

13

Frequent Chromosomal Aberrations by Array CGH Chromosomal aberration Overall (n=21) Skull base (n=2) Mobile spine (n=7) Sacrum (n=12) Loss of 1p Loss of 3p Loss of Loss of 5q4013 Gain of Loss of 9p Loss of 10q Loss of Loss of 13q13247 Loss of 14q Loss of 18q10235 Gain of Loss of 22q10145

Chromosomal Aberrations of Chordomas in Comparison to Chondrosarcoma Chromosomal aberration % Chordomas (n=21) % Chondrosarcoma (Rozeman et al., 2006) p-values (Fisher’s exact test; 2-tailed) Loss of 1p21/215/18<0.001 Loss of 3p20/212/18<0.001 Loss of 411/214/ Loss of 5q4/214/ Gain of 76/215/ Loss of 9p18/217/ Loss of 10q19/215/ Loss of 117/212/ Loss of 13q13/215/ Loss of 14q15/215/ Loss of 18q10/212/ Gain of 197/216/ Loss of 22q10/212/

VHL p16 PTEN RB SMAD4 NF2

Cen TP73 RUNX3 CDKN2C 1

Runx3 Actin Osteoblast GB60 Ch8 UCH1 Chordoma tissue

3 Loss 3p (only one orange signal Ch8

9

Hallor et al. 2008, British Journal of Cancer CDKN2A deletion commonly observed in Chordoma

p16 immunostaining

Cen A B 10

PTEN 10

PTEN

mTOR Signaling Pathway mTOR PROTEIN SYNTHESIS & CELL GROWTH S6 P S6K P 4EBP1 P Hamartin Tuberin Low Energy Ras MEK1/2 ERK1/2 RSK1 LKB1 AMPK Rheb PI3K Akt Growth Factor Stimulation P P PTEN rapamycin NF1 P P P

EGFR (55.0) Oncogenes on Chromosome 7 (7/22) BRAF (140.0) HGF (81.0) SMO (128.0) SHH (155.0) MET(116.0) Chordomas do not possess common cancer gene mutations

HDAC4 Actin Osteoblast GB60 CH8 UCH1 Met

miRNA-1 miRNA-1 targets: FoxP1 MET HDAC4 Decreased expression of miRNA-1 in chordoma

N1 N2 T2 T1 miRNA-1 miRNA- RNU48 N1 N2 T1 T2 miRNA-1 Relative Expression 28S 18S miRNA-1 N1N2 T1 T2 TC1 TC2 AB C D Real-time RT-PCR and Northern blot detection of mature miRNAs in chordoma

Absorbance (cell growth) Concentration of pre-miRNA-1 (nmol) miRNA-1 miRNA-control Hours after pre-miRNA transfection AB CD Met Actin miRNA-1 miRNA- control UCH1 Transfection of miRNA-1 into chordoma cells UCH1suppresses Met expression and inhibits cell growth

Expression of hepatocyte growth factor (HGF) and c-MET In skull based chordoma Naka, Kuester, Boltze, Scheil-Bertram, Samii,Herold, Ostertag, Krueger, Roessner Cancer 2008; 112:

Summary Chordomas have recurrent and remarkably stereotypic chromosomal profile 1p loss is observed in 100% of tumors 9p (CDKN2A; p16) or chromosome 9 loss was seen tumors (77%) Common losses also include 3p, 4, 10, 13, 14, 18, 22 Gains include 7, 19 These alterations point to genes for follow-up studies – therapies?

Thank you