Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer

TY - JOUR

T1 - Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer

AU - Krohn, Antje

AU - Freudenthaler, Fabian

AU - Harasimowicz, Silvia

AU - Kluth, Martina

AU - Fuchs, Sarah

AU - Burkhardt, Lia

AU - Stahl, Phillip

AU - C Tsourlakis, Maria

AU - Bauer, Melanie

AU - Tennstedt, Pierre

AU - Graefen, Markus

AU - Steurer, Stefan

AU - Sirma, Hüseyin

AU - Sauter, Guido

AU - Schlomm, Thorsten

AU - Simon, Ronald

AU - Minner, Sarah

PY - 2014/4/25

Y1 - 2014/4/25

N2 - TMPRSS2:ERG fusions, in combination with deletion of the phosphatase and tensin homolog (PTEN) tumor suppressor, have been suggested to cooperatively drive tumor progression in prostate cancer. We utilized a novel heterogeneity tissue microarray containing samples from 10 different tumor blocks of 189 prostatectomy specimens to study heterogeneity of genomic PTEN alterations in individual foci. PTEN alterations were found in 48/123 (39%) analyzable individual tumor foci, including 40 foci with deletions, 7 with deletion and rearrangement, and 1 focus with rearrangement only. PTEN was homogeneously aberrant in only 4 (8%) and heterogeneously in 44 (92%) of the foci. We found a specific sequence of molecular events from PTEN breakage followed by deletion of DNA sequences flanking the breakpoint, resulting in homozygous deletion. The observation that 16 of 19 foci with homogeneous ERG positivity had focal PTEN alterations but none of 10 foci with PTEN alterations had focal ERG positivity (P<0.0001) suggests that PTEN alterations typically develop subsequent to ERG fusions. We demonstrate a high level of intratumoral heterogeneity of PTEN alterations with deletions and rearrangements that challenges potential PTEN routine diagnosis testing in biopsies. The observation that PTEN alterations develop subsequent to ERG fusion strongly suggests that ERG expression may directly drive development of PTEN aberrations.Modern Pathology advance online publication, 25 April 2014; doi:10.1038/modpathol.2014.70.

AB - TMPRSS2:ERG fusions, in combination with deletion of the phosphatase and tensin homolog (PTEN) tumor suppressor, have been suggested to cooperatively drive tumor progression in prostate cancer. We utilized a novel heterogeneity tissue microarray containing samples from 10 different tumor blocks of 189 prostatectomy specimens to study heterogeneity of genomic PTEN alterations in individual foci. PTEN alterations were found in 48/123 (39%) analyzable individual tumor foci, including 40 foci with deletions, 7 with deletion and rearrangement, and 1 focus with rearrangement only. PTEN was homogeneously aberrant in only 4 (8%) and heterogeneously in 44 (92%) of the foci. We found a specific sequence of molecular events from PTEN breakage followed by deletion of DNA sequences flanking the breakpoint, resulting in homozygous deletion. The observation that 16 of 19 foci with homogeneous ERG positivity had focal PTEN alterations but none of 10 foci with PTEN alterations had focal ERG positivity (P<0.0001) suggests that PTEN alterations typically develop subsequent to ERG fusions. We demonstrate a high level of intratumoral heterogeneity of PTEN alterations with deletions and rearrangements that challenges potential PTEN routine diagnosis testing in biopsies. The observation that PTEN alterations develop subsequent to ERG fusion strongly suggests that ERG expression may directly drive development of PTEN aberrations.Modern Pathology advance online publication, 25 April 2014; doi:10.1038/modpathol.2014.70.

U2 - 10.1038/modpathol.2014.70

DO - 10.1038/modpathol.2014.70

M3 - SCORING: Journal article

C2 - 24762546

VL - 27

SP - 1612

EP - 1620

JO - MODERN PATHOL

JF - MODERN PATHOL

SN - 0893-3952

IS - 12

ER -