ATRX and TERT Alterations in Diffuse Gliomas
Transcript of ATRX and TERT Alterations in Diffuse Gliomas
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Disclosures
I have nothing to disclose
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ATRX and TERT Alterations in Diffuse Gliomas
Fundamental and Practical Implications
Tarik Tihan, MD, PhDProfessor of Pathology
UCSF School of Medicine
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Objectives BACKGROUND: CURRENT PATHOLOGICAL
APPROACH TO DIFFUSE GLIOMAS
THE ASTROCYTOMA MOLECULAR SUBTYPE
AND RELEVANCE OF ATRX AND ALTERNATE
LENGTHENING OF TELOMERES
TELOMERES AND TELOMERASE (TERT)
PROMOTER MUTATIONS IN GLIOBLASTOMA
AND OLIGODENDROGLIOMA
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The Haarlem Consensus
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Histologic classification
Diffuse astrocytoma Oligodendroglioma
“Oligoastrocytoma” or ambiguous
histology
Molecular
IDH-mut, 1p/19q-nondel,
ATRX loss
Diffuse astrocytoma
Diffuse glioma (oligo phenotype)
Diffuse astrocytoma
IDH-mut, 1p/19q-codel, ATRX intact
Diffuse glioma (astrocytoma phenotype)
Oligodendroglioma Oligodendroglioma
IDH wild typeDiffuse
astrocytoma, IDH wild type*
Diffuse glioma, IDH wild type
Diffuse astrocytoma,
IDH wild type*Testing not performed
Diffuse astrocytoma,
NOS
Oligodendroglioma, NOS
“Diffuse glioma, NOS”
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ATRX AND ALTERNATE LENGTHENING OF TELOMERES (ALT)
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ATRX/DAXX complex and Histone Proteins
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10
ATRX
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Pekmezci et al. UCSF Adult Glioma Study
• Adult Glioma Study cases (1997-2012)• Cases with IDH and TERT promoter mutation
sequencing results• Tumors with and without ATRX loss stratified
according to Age and other mutations
• 399 patients202 WHO Grade IV
48 WHO Grade III149 WHO Grade II
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Histologic Type and Age Based on ATRX Status
PEKMEZCI et al.
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Age and IDH Mutations Based on ATRX Status
47,6
54,8
43,5
36,6
39,7
35,9
30
35
40
45
50
55
60ATRX‐WT
ATRX‐Mut
IDH-WTALL IDH-MutPEKMEZCI et al.
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Survival of IDH Wild-Type Tumors Based on ATRX Status
P=0.0013IDH-WT tumors
ATRX-WT
ATRX-MUT
PEKMEZCI et al.
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ATRX• Loss of protein or loss of function mutation
is associated with IDH mutations• ATRX mutation/loss occurs in a younger
age group of patients regardless of IDH status or Grade
• ATRX appears to be a later molecular event and often succeeds early genetic aberrations.
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TELOMERES AND TELOMERASE
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COURTESY OF DR. MELIKE PEKMEZCI, UCSF
TERT Mutations
• C228T ~ 75% • C250T ~ 25%• glioblastomas and oligodendrogliomas
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42,6
50,5
37,3
52,4
57,3
43,7
30
35
40
45
50
55
60TERT‐WTTERT‐Mut
ALL IDH-WT IDH-MutPEKMEZCI et al.
Age and IDH Mutations Based on TERT Status
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TERT and/or Age
Effect Chi-Square P Hazard Ratio
Age (per year) 19.9 <0.0001 1.033
TERT-mutation 2.7 0.1 1.33
Gender (female) 0.07 0.8 0.96
• Age is the main factor for poor prognosis
• Negative prognostic effect of TERT mutation for older age at diagnosis
IDH-WT tumors
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TERT and/or Age
Effect Chi-Square P Hazard Ratio
Age (per year) 6.59 0.01 1.035
TERT-mutation 25 <0.0001 0.213
Gender (female) 0.13 0.72 1.1
• TERT mutation is the main factor for favorable prognosis
• Positive prognostic effect of TERT mutation for younger age at diagnosis
IDH-MUT tumors
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From Jenkins et al. unpublished data
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CONCLUSIONS TERT mutations often involve C228T and
C250T mutations of the promoter region TERT mutations occur in
OLIGODENDROGLIOMA and GLIOBLASTOMA
TERT promoter mutations are mutually exclusive with ATRX mutations
IDH mutant, TERT positive tumors are younger, IDH wild-type and TERT positive tumors are older
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CONCLUSIONS
ATRX loss in immunohistochemistry should be used routinely for classification of adult diffuse gliomas
ATRX mutations are almost always accompanied by other mutations in the histone regulation (IDH, H33 K27M, TP53 etc)
The key aberration is the Alternate Lengthening of Telomeres and a better marker may be coming in the future