TY - JOUR
T1 - High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma
AU - Nasu, Masaki
AU - Emi, Mitsuru
AU - Pastorino, Sandra
AU - Tanji, Mika
AU - Powers, Amy
AU - Luk, Hugh
AU - Baumann, Francine
AU - Zhang, Yu An
AU - Gazdar, Adi
AU - Kanodia, Shreya
AU - Tiirikainen, Maarit
AU - Flores, Erin
AU - Gaudino, Giovanni
AU - Becich, Michael J.
AU - Pass, Harvey I.
AU - Yang, Haining
AU - Carbone, Michele
N1 - Publisher Copyright:
© 2015 by the International Association for the Study of Lung Cancer.
PY - 2015/4/30
Y1 - 2015/4/30
N2 - Background: Breast cancer 1-associated protein 1 (BAP1) is a nuclear deubiquitinase that regulates gene expression, transcription, DNA repair, and more. Several findings underscore the apparent driver role of BAP1 in malignant mesothelioma (MM). However, the reported frequency of somatic BAP1 mutations in MM varies considerably, a discrepancy that appeared related to either methodological or ethnical differences across various studies. Methods: To address this discrepancy, we carried out comprehensive genomic and immunohistochemical (IHC) analyses to detect somatic BAP1 gene alterations in 22 frozen MM biopsies from U.S. MM patients. Results: By combining Sanger sequencing, multiplex ligation-dependent probe amplification, copy number analysis, and cDNA sequencing, we found alteration of BAP1 in 14 of 22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the eight MM containing wild-type BAP1, whereas no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1. Thus, IHC results were in agreement with those obtained by genomic analyses. We then extended IHC analysis to an independent cohort of 70 MM biopsies, of which there was insufficient material to perform molecular studies. IHC revealed loss of BAP1 nuclear staining in 47 of these 70 MM biopsies (67.1%). Conclusions: Our findings conclusively establish BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or other clinical characteristics. Our data point to IHC as the most accessible and reliable technique to detect BAP1 status in MM biopsies.
AB - Background: Breast cancer 1-associated protein 1 (BAP1) is a nuclear deubiquitinase that regulates gene expression, transcription, DNA repair, and more. Several findings underscore the apparent driver role of BAP1 in malignant mesothelioma (MM). However, the reported frequency of somatic BAP1 mutations in MM varies considerably, a discrepancy that appeared related to either methodological or ethnical differences across various studies. Methods: To address this discrepancy, we carried out comprehensive genomic and immunohistochemical (IHC) analyses to detect somatic BAP1 gene alterations in 22 frozen MM biopsies from U.S. MM patients. Results: By combining Sanger sequencing, multiplex ligation-dependent probe amplification, copy number analysis, and cDNA sequencing, we found alteration of BAP1 in 14 of 22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the eight MM containing wild-type BAP1, whereas no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1. Thus, IHC results were in agreement with those obtained by genomic analyses. We then extended IHC analysis to an independent cohort of 70 MM biopsies, of which there was insufficient material to perform molecular studies. IHC revealed loss of BAP1 nuclear staining in 47 of these 70 MM biopsies (67.1%). Conclusions: Our findings conclusively establish BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or other clinical characteristics. Our data point to IHC as the most accessible and reliable technique to detect BAP1 status in MM biopsies.
KW - BAP1
KW - Malignant mesothelioma
KW - Somatic BAP1 mutation
KW - Sporadic malignant mesothelioma
KW - multiplex ligation-dependent probe amplification
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U2 - 10.1097/JTO.0000000000000471
DO - 10.1097/JTO.0000000000000471
M3 - Article
C2 - 25658628
AN - SCOPUS:84938286152
SN - 1556-0864
VL - 10
SP - 565
EP - 576
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 4
ER -