TY - JOUR
T1 - Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma
AU - Xu, Jinfei
AU - Kadariya, Yuwaraj
AU - Cheung, Mitchell
AU - Pei, Jianming
AU - Talarchek, Jacqueline
AU - Sementino, Eleonora
AU - Tan, Yinfei
AU - Menges, Craig W.
AU - Cai, Kathy Q.
AU - Litwin, Samuel
AU - Peng, Hongzhuang
AU - Karar, Jayashree
AU - Rauscher, Frank J.
AU - Testa, Joseph R.
N1 - ©2014 American Association for Cancer Research.
PY - 2014/8/15
Y1 - 2014/8/15
N2 - Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germlineinactivating mutations of BAP1 predispose to mesothelioma and certain other cancers. However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers are not known. To address these questions experimentally, we generated a Bap1+/- knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1+/- mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than wild-type (WT) littermates (73% vs. 32%, respectively). Furthermore, mesotheliomas arose at an accelerated rate in Bap1+/- mice than in WT animals (median survival, 43 weeks vs. 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1+/- mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1+/- mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in WT mice, mesotheliomas from Bap1+/- mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1+/- mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1+/- mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb. Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure.
AB - Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germlineinactivating mutations of BAP1 predispose to mesothelioma and certain other cancers. However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers are not known. To address these questions experimentally, we generated a Bap1+/- knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1+/- mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than wild-type (WT) littermates (73% vs. 32%, respectively). Furthermore, mesotheliomas arose at an accelerated rate in Bap1+/- mice than in WT animals (median survival, 43 weeks vs. 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1+/- mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1+/- mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in WT mice, mesotheliomas from Bap1+/- mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1+/- mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1+/- mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb. Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure.
KW - Animals
KW - Asbestos/toxicity
KW - Disease Models, Animal
KW - Epigenomics
KW - Female
KW - Genetic Predisposition to Disease
KW - Genotype
KW - Germ-Line Mutation
KW - Lung Neoplasms/etiology
KW - Mesothelioma, Malignant
KW - Mesothelioma/etiology
KW - Mice
KW - Mice, Knockout
KW - Tumor Suppressor Proteins/genetics
KW - Ubiquitin Thiolesterase/genetics
UR - http://www.scopus.com/inward/record.url?scp=84905986583&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000341186700018&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1158/0008-5472.CAN-14-1328
DO - 10.1158/0008-5472.CAN-14-1328
M3 - Article
C2 - 24928783
SN - 0008-5472
VL - 74
SP - 4388
EP - 4397
JO - Cancer Research
JF - Cancer Research
IS - 16
ER -