Regular article
Molecular pathogenesis of genetic and inherited diseases
Hypersensitivities for Acetaldehyde and Other Agents among Cancer Cells Null for Clinically Relevant Fanconi Anemia Genes

https://doi.org/10.1016/j.ajpath.2013.09.023Get rights and content
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Large-magnitude numerical distinctions (>10-fold) among drug responses of genetically contrasting cancers were crucial for guiding the development of some targeted therapies. Similar strategies brought epidemiological clues and prevention goals for genetic diseases. Such numerical guides, however, were incomplete or low magnitude for Fanconi anemia pathway (FANC) gene mutations relevant to cancer in FANC-mutation carriers (heterozygotes). We generated a four-gene FANC-null cancer panel, including the engineering of new PALB2/FANCN-null cancer cells by homologous recombination. A characteristic matching of FANCC-null, FANCG-null, BRCA2/FANCD1-null, and PALB2/FANCN-null phenotypes was confirmed by uniform tumor regression on single-dose cross-linker therapy in mice and by shared chemical hypersensitivities to various inter-strand cross-linking agents and γ-radiation in vitro. Some compounds, however, had contrasting magnitudes of sensitivity; a strikingly high (19- to 22-fold) hypersensitivity was seen among PALB2-null and BRCA2-null cells for the ethanol metabolite, acetaldehyde, associated with widespread chromosomal breakage at a concentration not producing breaks in parental cells. Because FANC-defective cancer cells can share or differ in their chemical sensitivities, patterns of selective hypersensitivity hold implications for the evolutionary understanding of this pathway. Clinical decisions for cancer-relevant prevention and management of FANC-mutation carriers could be modified by expanded studies of high-magnitude sensitivities.

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Supported by NIH grants CA62924 and CA123483 and The Everett and Marjorie Kovler Professorship in Pancreas Cancer Research (all to S.E.K.). The breakage studies were supported by The Kennedy Krieger Intellectual & Developmental Disabilities Research Center grant 5P30 HD024061-22 (Michael Cataldo, Director, Department of Behavioral Psychology, Kennedy Krieger Institute, Baltimore, MD).