Increase, Chromosomal aberrations leads to Increase, lung cancer

Uncertainties and inconsistencies in this KER are as follows:

1. CNVs are often difficult to detect in cancer cells, even with current advances in next generation sequencing. This is due to the sheer number of CNVs that could possibly be present within one tumour; the unknown ratio of cancer cells and healthy cells within a tumour sample; the unknown ploidy of tumours; and the possible presence of multiple clones in one tumour, including possible low-number subclones that may be difficult to detect (Liu et al. 2013).  
2. In some studies, smoking does not affect the CA-cancer relationship (Bonassi et al. 2000; Bonassi et al. 2008; El-zein et al. 2014; Vodenkova et al. 2015; El-zein et al. 2017), but it does have a significant effect in other studies (Paik et al. 2012; Lloyd et al. 2013; Minina et al. 2017).
3. In a study examining MN in lung fibroblasts isolated from Wistar rats and Syrian hamsters exposed to radon, Syrian hamsters were found to have a significantly increased rate of MN per 1000 bincleated cells per Gy relative to rats. According to the literature however, Wistar rats have a higher documented sensitivity to radon-induced lung cancer than Syrian hamsters (Khan et al. 1995).

There is evidence of a response-response relationship between radiation exposure and CAs in cells of the lung, and between radiation exposure and the risk of lung cancer in radon-exposed miners. In two different studies using lung fibroblasts isolated from irradiated rodents, there was a positive, linear, dose-dependent relationship found between the radiation dose and the number of MN (Brooks et al. 1995; Khan et al. 1995). A number of in vitro studies also confirmed the presence of a positive, linear dose-dependent relationship between the number of radiation-induced CAs and the radiation dose (Nagasawa et al. 1990; Yamada et al. 2002; Stevens et al. 2014). In studies examining mortality from lung cancer in radon-exposed uranium miners from France and Germany, there was a positive linear relationship between the radon exposure and risk of lung cancer mortality (Tirmarchel et al. 1993; Walsh et al. 2010). This relationship was found to be exponentially modified by the age at median exposure, the time since median exposure, and the radon exposure rate (Walsh et al. 2010). Furthermore, oncogenic transformations in C3H10T1/2 cells irradiated with alpha particles were found to increase in a positive, linear dose-dependent fashion (Miller et al. 1996).

There is evidence suggesting that time-related predictions can be made for CA incidence and the development of lung cancer after exposure to ionizing radiation. CAs have been demonstrated to occur within hours of irradiation and persist for days afterwards.  In mouse bronchial epithelial cells, 1 Gy of X-ray radiation induced a significant increase in the percentage of binucleated cells with MN by 24 hours post-irradiation. These levels remained significantly elevated at 48 hours and 72 hours post-irradiation, though there was a time-dependent decrease in the percentage of cells with CAs. By 7 days post-irradiation, these levels were no longer significantly different from controls (Werner et al. 2017). In a similar study, lung fibroblasts were isolated and cultured from Wistar rats, Syrian hamsters and Chinese hamsters after exposure to 323, 278 and 496 WLM of radon, respectively, at 0.2, 15, and 30 days post-exposure. In all species, MN levels were highest at 0.2 days post-irradiation, and decreased over 30 days. The MN levels in the irradiated fibroblasts, however, remained significantly elevated at all time points relative to unirradiated control cells (Khan et al. 1995). Other in vitro studies have shown the presence of CAs within 13 - 82 hours post-irradiation (Nagasawa et al. 1990; Deshpande et al. 1996; Yamada et al. 2002; Stevens et al. 2014). It was noted in one study that the number or sister chromatid exchanges per cell were significantly higher than non-irradiated control cells at 72 hr post-irradiation, but these levels did not change appreciably at 74, 76, 78 or 82 hours post-irradiation (Deshpande et al. 1996).

In comparison to the time between radiation exposure and CA detection, there is a much longer gap between radiation exposure and the incidence of lung cancer. Oncogenic transformations in fibroblasts irradiated with alpha particles or X-rays were present 4 - 8 weeks after radiation exposure (Robertson et al. 1983; Miller et al. 1996). In vivo irradiation of 1 week-, 5 week- and 15 week-old rats by 1 Gy of thoracic X-rays was found to induce lung tumours months to years after the radiation treatment, with the highest risk for lung tumours found in rats that died between 600 and 900 days of age (Yamada et al. 2017). Similarly, French uranium miners exposed to radon and radon progeny for a minimum of two years were diagnosed at least 10 years after the first radon exposure (Tirmarchel et al. 1993).

Furthermore, direct injection of a CA into mice has also been shown to result in cancer several weeks after the CA administration. Injection of tumourigenic A549 cells that harbour a loss of heterozygosity at chromosome 11 resulted in tumour growth 3 weeks after injection (Kuramochi et al. 2001). Similarly, administration of the BCR/ABL translocation resulted in the mouse equivalent of chronic myelogenous leukemia by 21 - 31 days post-injection (Pear et al. 1998).

Not identified.