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Resorting the function of the colorectal cancer gatekeeper adenomatous polyposis coli
Author(s) -
Kariv Revital,
Caspi Michal,
FlissIsakov Naomi,
Shorer Yamit,
Shor Yarden,
Rosner Guy,
Brazowski Eli,
Beer Gil,
Cohen Shlomi,
RosinArbesfeld Rina
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32557
Subject(s) - nonsense mutation , familial adenomatous polyposis , adenomatous polyposis coli , adenoma , medicine , colorectal cancer , cancer research , nonsense , cancer , mutation , oncology , gene , biology , genetics , missense mutation
As a large number of cancers are caused by nonsense mutations in key genes, read‐through of these mutations to restore full‐length protein expression is a potential therapeutic strategy. Mutations in the adenomatous polyposis coli (APC) gene initiate the majority of both sporadic and hereditary colorectal cancers (CRC) and around 30% of these mutations are nonsense mutations. Our goal was to test the feasibility and effectiveness of APC nonsense mutation read‐through as a potential chemo‐preventive therapy in Familial Adenomatous Polyposis (FAP), an inherited CRC syndrome patients. Ten FAP patients harboring APC nonsense mutations were treated with the read‐through inducing antibiotic erythromycin for 4 months. Endoscopic assessment of the adenomas was performed at baseline, after 4 and after 12 months. Adenoma burden was documented in terms of adenoma number, maximal polyp size and cumulative polyp size per procedure. Tissue samples were collected and subjected to molecular and genetic analyses. Our results show that in the majority of patients the treatment led to a decrease in cumulative adenoma burden, median reduction in cumulative adenoma size and median reduction in adenoma number. Molecular and genetic analyses of the adenomas revealed that the treatment led to a reduced number of somatic APC mutations, reduced cellular proliferation and restoration of APC tumor‐suppressing activity. Together, our findings show that induced read‐through of APC nonsense mutations leads to promising clinical results and should be further investigated to establish its therapeutic potential in FAP and sporadic CRCs harboring nonsense APC mutations.