Chromosomal radiosensitivity as a marker of predisposition to common cancers?

Abstract

SummaryWe previously found that 40% of breast cancer patients showed enhanced sensitivity to X-ray induced chromosome damage in G 2 lymphocytes and suggested that this might indicate a low penetrance predisposition to breast cancer, for which there is good epidemiological evidence. We have now tested the hypothesis that elevated G 2 radiosensitivity is a marker of such predisposition to other common cancers. We tested patients with colorectal cancer, for which there is also good epidemiological evidence of inherited risk in a substantial proportion of cases, and patients with cancers having a strong environmental aetiology (lung and cervix). We also repeated our study of breast cancer cases and tested patients with chronic diseases other than cancer. The results support our hypothesis, in that 30% (12/37) of colorectal cases showed enhanced sensitivity compared with 9% (6/66) of normal healthy controls (P = 0.01), whereas the proportions of sensitive cervix (11%, 3/27, P = 0.72) and lung cancer cases (23%, 8/35, P = 0.07) were not significantly above normals. We confirmed the enhanced sensitivity of 40% (12/31, P = 0.001) of breast cancer patients and found that patients with non-malignant disease had a normal response in the assay (12%, 4/34, P = 0.73). We suggest that enhanced G 2 chromosomal radiosensitivity is a consequence of inherited defects in the ability of cells to process DNA damage from endogenous or exogenous sources, of a type that is mimicked by ionizing radiation, and that such defects predispose to breast and colorectal cancer.

Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition

“…In breast cancer patients the elevated chromosomal radiosensitivity is confirmed in several independent studies (Scott et al, 1994(Scott et al, , 1998Parshad et al, 1996;Patel et al, 1997;Terzoudi et al, 2000;Baria et al, 2001a;Riches et al, 2001). In these studies the G2 assay, which involves the analysis of chromatid breaks in metaphase cells that are irradiated during the G2 phase of the cell cycle, was used to evaluate chromosomal radiosensitivity.…”

Chromosomal radiosensitivity in head and neck cancer patients: evidence for genetic predisposition?

“…Several studies have shown that enhanced chromosomal radiosensitivity is also present in a significant proportion of cancer patients (Scott et al, 1994(Scott et al, , 1998Parshad et al, 1996;Patel et al, 1997;Terzoudi et al, 2000;Baria et al, 2001Baria et al, , 2002Buchholz and Wu, 2001;Papworth et al, 2001;Riches et al, 2001;Baeyens et al, 2002Baeyens et al, , 2005Ban et al, 2004;Howe et al, 2005;Kolusayin Ozar and Orta, 2005;Mozdarani et al, 2005;Distel et al, 2006;Lisowska et al, 2006;Varga et al, 2006). The majority of data have been collected in studies considering breast cancer patients whose lymphocytes were irradiated in the G 2 phase of the cell cycle (Scott et al, 1994Parshad et al, 1996;Patel et al, 1997;Terzoudi et al, 2000;Baria et al, 2001;Buchholz and Wu, 2001;Riches et al, 2001;Baeyens et al, 2002Baeyens et al, , 2005Howe et al, 2005;Djuzenova et al, 2006;Docherty et al, 2007). In a high number of these studies, it was found that approximately 40% of breast cancer patients show an increased G 2 chromosomal radiosensitivity (Scott et al, 1994Baria et al, 2001;Buchholz and Wu, 2001;Riches et al, 2001;Baeyens et al, 2002Baeyens et al, , 2005.…”

A role for topoisomerase IIα in the formation of radiation-induced chromatid breaks

“…Our results indicate the indirect involvement of topoisomerase IIa in the formation of radiation-induced chromatid breaks from DSB, and suggest topoisomerase IIa as a possible factor in the inter-individual variation in chromatid radiosensitivity. British Journal of Cancer (2008) Human response to low doses of ionising radiation shows a wide variation as exemplified by the different frequencies of radiationinduced chromatid breaks observed in metaphase chromosomes in phytohaemagglutinin-stimulated peripheral blood T-lymphocytes (PBL) from different normal individuals and sporadic cancer cases, and elevated frequencies of such chromatid breaks have been linked to cancer susceptibility (Scott et al, 1994(Scott et al, , 1996Roberts et al, 1999;Baria et al, 2001Baria et al, , 2002Buchholz and Wu, 2001;Riches et al, 2001;Papworth et al, 2001;Smart et al, 2003;Baeyens et al, 2002Baeyens et al, , 2005. Using a short time interval (1-2 h) between radiation exposure and sampling, the metaphase cells (blocked with colcemid) collected are those that were in the G2-phase of the cell cycle at the time of exposure and show frequent chromatid breaks (discontinuities or terminal deletions) that have been shown to be induced as a linear function of radiation dose (Bryant, 1998).…”