title: RADIOSENSITIVITY TO HIGH ENERGY IRON IONS IS INFLUENCED BY HETEROZYGOSITY forATM, RAD9andBRCA1.
abstract: Loss of function of DNA repair genes has been implicated in the development of many types of cancer. In the last several years, heterozygosity leading to haploinsufficiency for proteins involved in DNA repair was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced, for example by ionizing radiation. Since the effect of heterozygosity for one gene is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes critical to pathways that control DNA damage signaling, repair or apoptosis. We investigated the role of heterozygosity forAtm,Rad9andBrca1on cell oncogenic transformation and cell survival induced by 1GeV/n56Fe ions. Our results show that cells heterozygous for bothAtmandRad9orAtmandBrca1have high survival rates and are more sensitive to transformation by high energy Iron ions when compared with wild-type controls or cells haploinsufficient for only one of these proteins. Since mutations or polymorphisms for similar genes exist in a small percentage of the human population, we have identified a radiosensitive sub-population. This finding has several implications. First, the existence of a radiosensitive sub-population may distort the shape of the dose-response relationship. Second, it would not be ethical to put exceptionally radiosensitive individuals into a setting where they may potentially be exposed to substantial doses of radiation.
authors.affiliation: Center for Radiological Research, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Center for Radiological Research, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Smilenov
authors.affiliation: Center for Radiological Research, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: H B
authors.initials: HB
authors.lastname: Lieberman
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ludwig
authors.affiliation: Center for Radiological Research, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Hall