title: Hypersensitivities for acetaldehyde and other agents among cancer cells null for clinically relevant Fanconi anemia genes.
abstract: 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.
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Soma
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Howard Hughes Medical Institute and the Ludwig Center for Cancer Genetics and Therapeutics, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Surojit
authors.initials: S
authors.lastname: Sur
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Sashidhar R
authors.initials: SR
authors.lastname: Yerram
authors.affiliation: Howard Hughes Medical Institute and the Ludwig Center for Cancer Genetics and Therapeutics, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rago
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Bhunia
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: M Zulfiquer
authors.initials: MZ
authors.lastname: Hossain
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Bogdan C
authors.initials: BC
authors.lastname: Paun
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Yunzhao R
authors.initials: YR
authors.lastname: Ren
authors.affiliation: Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Nilofer A
authors.initials: NA
authors.lastname: Azad
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. Electronic address: sk@jhmi.edu.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Kern
mesh_terms: D000079:Acetaldehyde / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005199:Fanconi Anemia / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D051856:Fanconi Anemia Complementation Group Proteins; D000079:Acetaldehyde