Disclosures

I have nothing to disclose

ATRX and TERT Alterations in Diffuse Gliomas

Fundamental and Practical Implications

Tarik Tihan, MD, PhDProfessor of Pathology

UCSF School of Medicine

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

The Haarlem Consensus

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”

ATRX AND ALTERNATE LENGTHENING OF TELOMERES (ALT)

ATRX/DAXX complex and Histone Proteins

10

ATRX

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

Histologic Type and Age Based on ATRX Status

PEKMEZCI et al.

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.

Survival of IDH Wild-Type Tumors Based on ATRX Status

P=0.0013IDH-WT tumors

ATRX-WT

ATRX-MUT

PEKMEZCI et al.

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.

TELOMERES AND TELOMERASE

COURTESY OF DR. MELIKE PEKMEZCI, UCSF

TERT Mutations

• C228T ~ 75% • C250T ~ 25%• glioblastomas and oligodendrogliomas

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

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

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

From Jenkins et al. unpublished data

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

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