TY - JOUR
T1 - Clinical assessment of PTEN loss in endometrial carcinoma
T2 - Immunohistochemistry outperforms gene sequencing
AU - Djordjevic, Bojana
AU - Hennessy, Bryan T.
AU - Li, Jie
AU - Barkoh, Bedia A.
AU - Luthra, Rajyalakshmi
AU - Mills, Gordon B.
AU - Broaddus, Russell R.
N1 - Funding Information:
We acknowledge NIH 2P50 CA098258-06 SPORE in Uterine Cancer (RRB) and Stand Up to Cancer/ American Association for Cancer Research Dream Team Translational Cancer Research Grant, Grant No. SU2C-AACR-DT0209 (RRB, BTH, and GBM), and MD Anderson Cancer Center Support Grant (CCSG) CA016672 from National Institutes of Health. We also thank Michelle Hildebrandt, PhD, Department of Epidemiology, MD Anderson Cancer Center, for her helpful discussion regarding this manuscript and to Su-Su Xie, MD, for technical assistance.
PY - 2012/5
Y1 - 2012/5
N2 - PTEN (phosphatase and tensin homolog) is a tumor suppressor that negatively regulates the PI3K-AKT signaling pathway, which is implicated in the pathogenesis of endometrial carcinoma. Sanger sequencing has been considered to be the gold standard for detection of PTEN sequence abnormalities. However, this approach fails to address the epigenetic mechanisms that contribute to functional PTEN loss. Using a study cohort of 154 endometrioid and non-endometrioid endometrial carcinomas, we performed full-length PTEN sequencing and PTEN immunohistochemistry on each tumor. PTEN sequence abnormalities were detected in a significantly lower proportion of cases (43%) than PTEN protein loss (64%, P=0.0004). Endometrioid tumors had a significantly higher proportion of PTEN sequence abnormalities and PTEN protein loss than non-endometrioid tumors. Within the latter group, PTEN sequence abnormalities and PTEN protein loss were most frequent in undifferentiated carcinomas, followed by mixed carcinomas; they were least frequent in carcinosarcomas. Overall, at least one PTEN sequence abnormality was detected in each exon, and the greatest number of sequence abnormalities was detected in exon 8. Pure-endometrioid tumors had a significantly higher frequency of sequence abnormalities in exon 7 than did the non-endometrioid tumors (P0.0199). Importantly, no mutational hotspots were identified. While PTEN protein loss by immunohistochemistry was identified in 89% of cases with a PTEN sequence abnormality, PTEN protein loss was detected by immunohistochemistry in 44% of cases classified as PTEN wild type by sequencing. For the first time, we demonstrate that PTEN immunohistochemistry is able to identify the majority of cases with functional PTEN loss. However, PTEN immunohistochemistry also detects additional cases with PTEN protein loss that would otherwise be undetected by gene sequencing. Therefore, for clinical purposes, immunohistochemistry appears to be a preferable technique for identifying endometrial tumors with loss of PTEN function.
AB - PTEN (phosphatase and tensin homolog) is a tumor suppressor that negatively regulates the PI3K-AKT signaling pathway, which is implicated in the pathogenesis of endometrial carcinoma. Sanger sequencing has been considered to be the gold standard for detection of PTEN sequence abnormalities. However, this approach fails to address the epigenetic mechanisms that contribute to functional PTEN loss. Using a study cohort of 154 endometrioid and non-endometrioid endometrial carcinomas, we performed full-length PTEN sequencing and PTEN immunohistochemistry on each tumor. PTEN sequence abnormalities were detected in a significantly lower proportion of cases (43%) than PTEN protein loss (64%, P=0.0004). Endometrioid tumors had a significantly higher proportion of PTEN sequence abnormalities and PTEN protein loss than non-endometrioid tumors. Within the latter group, PTEN sequence abnormalities and PTEN protein loss were most frequent in undifferentiated carcinomas, followed by mixed carcinomas; they were least frequent in carcinosarcomas. Overall, at least one PTEN sequence abnormality was detected in each exon, and the greatest number of sequence abnormalities was detected in exon 8. Pure-endometrioid tumors had a significantly higher frequency of sequence abnormalities in exon 7 than did the non-endometrioid tumors (P0.0199). Importantly, no mutational hotspots were identified. While PTEN protein loss by immunohistochemistry was identified in 89% of cases with a PTEN sequence abnormality, PTEN protein loss was detected by immunohistochemistry in 44% of cases classified as PTEN wild type by sequencing. For the first time, we demonstrate that PTEN immunohistochemistry is able to identify the majority of cases with functional PTEN loss. However, PTEN immunohistochemistry also detects additional cases with PTEN protein loss that would otherwise be undetected by gene sequencing. Therefore, for clinical purposes, immunohistochemistry appears to be a preferable technique for identifying endometrial tumors with loss of PTEN function.
KW - PTEN
KW - endometrial cancer
KW - immunohistochemistry
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U2 - 10.1038/modpathol.2011.208
DO - 10.1038/modpathol.2011.208
M3 - Article
C2 - 22301702
AN - SCOPUS:84862777505
SN - 0893-3952
VL - 25
SP - 699
EP - 708
JO - Modern Pathology
JF - Modern Pathology
IS - 5
ER -