To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:1985
Increase, Chromosomal aberrations leads to Increase, lung cancer
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Chromosomal aberrations (CAs) are described as irregularities in chromosome structure due to segments of the chromosome that have been lost, gained, or rearranged. This can lead to two categories of chromosomal exchanges: balanced, which do not impact the overall frame of chromosome structure, and unbalanced, which refers to CAs that do alter the frame of chromosome structure (Genetic Alliance 2010) . Specific categories of CAs include chromosome-type aberrations (CSAs) such as chromosome-type breaks, ring chromosomes, marker chromosomes, and dicentric aberrations; chromatid-type aberrations (CTAs) such as chromatid breaks and chromatid exchanges (Hagmar et al. 2004; Bonassi et al. 2008); micronuclei (MN); nucleoplasmic bridges (NPBs); and copy number variants (CNVs). When CAs affect genes related to tumourigenesis or their regulatory regions (Shlien and Malkin 2009; Liu et al. 2013), this may lead to an abnormal accumulation of malignant cells and ultimately may result in cancer. Lung cancer in particular may occur if these tumourigenesis-related CAs (which are more often unbalanced than balanced in lung cancer (Mitelman et al. 1997) occur in cells of the lung.
Evidence Supporting this KER
The biological rationale linking CAs with lung cancer is strongly supported. There are many epidemiological studies that provide evidence of a link between increasing CAs and cancer incidence. Several published reports spanning over 22,000 study subjects across multiple European countries have examined the association between the presence of CAs in cultured blood lymphocytes and the incidence of cancer. In every cohort examined, the presence of CAs was predictive of cancer risk (Bonassi et al. 2000; Hagmar et al. 2004; Norppa et al. 2006; Boffetta et al. 2007; Bonassi et al. 2008). Although CSAs and CTAs both had predictive value, CSAs were considered to be slightly more indicative of cancer risk (Norppa et al. 2006). Similarly, studies examining chromosomes in lymphocytes from lung cancer patients found significant increases in CTAs, CSAs, and overall CAs relative to lymphocytes from healthy controls. Furthermore, the CAs were shown to be significant predictors of lung cancer risk (Vodenkova et al. 2015). Analysis of MN and NPB levels within binucleated cells also found that these CAs were significantly increased in lung cancer patients relative to healthy controls (Lloyd et al. 2013; El-zein et al. 2014; El-zein et al. 2017), with very similar results for geographically-separated test and validation cohorts (El-zein et al. 2014).
Exposure to radiation has also been epidemiologically linked to the relationship between CAs and cancer. Studies of radon-exposed uranium miners have revealed evidence of an association between exposure to radon gas and an increased incidence of lung cancer (Roscoe et al. 1989; Tirmarchel et al. 1993; Smerhovsky et al. 2001; Smerhovsky et al. 2002; Vacquier et al. 2008; Walsh et al. 2010). Analysis of CAs in the blood lymphocytes of miners from the Czech Republic found that miners with higher levels of CAs had a significantly elevated risk of cancer (Smerhovsky et al. 2001; Smerhovsky et al. 2002). The results from these studies were likely not due to smoking status of the miners, as a study examining a cohort of 516 white, never-smoker American uranium miners found that the mortality rates from lung cancer were higher in the miners than in the general non-smoking population (Roscoe et al. 1989).
Beyond epidemiology, there are also many genetic and molecular studies that provide strong evidence of a relationship between CAs and cancer. A subset of these studies have investigated copy number variants (CNVs). Examination of CNVs and known cancer genes in a large population revealed that CNVs often overlap with cancer genes and thus have the potential to amplify carcinogenesis (Shlien and Malkin 2009; Ohshima et al. 2017)Moreover, using only CNV genetic information from a database, Zhang et al (2016) were able to categorize 3,480 samples into their respective cancer type based solely on the CNVs of the samples. This was accomplished by developing a panel of 19 discriminating genes that could predict cancer type with a high level of accuracy using only the CNV number. Interestingly, many of these discriminating genes have known associations with cancer or processes known to be important in cancer development (Zhang et al. 2016). Furthermore, cancer-prone individuals tend to have more CNV instability, which has been attributed to inherently less efficient DNA repair mechanisms (Shlien and Malkin 2009). In their 2013 review, Liu et al provided lists of cancer-related genes typically amplified by CNVs (ERBB2, EGFR, MYC, PIK3CA, IGF1R, FGFR1/2, KRAS, CDK4, CCDN1, MDM2, MET, and CDK6) and deleted by CNVs (RB1, PTEN, CDKN2A/B, ARID1A, MAPSK4, NF1, SMAD4, BRCA1/2, MSH2/6, DCC, and CDH1). There is also evidence associating CNVs to lung cancer specifically. Analysis of primary NSCLC samples revealed 27 chromosomal regions where CNVs were present in at least one third of the samples (Wrage et al. 2009). Furthermore, medically-relevant CNVs were found in 60% of lung cancer patients, encompassing genes such as TP53, BAP1, STK11, BRCA2, CDKN2A, and RB1 (Mukherjee et al. 2016).
Likewise, lung cancer-specific studies have been performed to identify chromosomes most often affected by CNV gains and losses. Analysis of DNA from primary human lung tumours and early-passage primary cell lines established from human tumours revealed that gains were most frequently found at chromosomes 3q, 5p, 7p, and 8q, while losses were most frequent at chromosome 3p (Balsara et al. 1997). Separation of CNV analyses into squamous cell carcinoma and lung adenocarcinoma groups demonstrated differences between the two lung cancers (Petersen et al. 1997; Bjorkqvist et al. 1998; Feder et al. 1998; Massion et al. 2002). In general, CNV changes were present in 84% of squamous cell carcinoma samples, but only in 68% of adenocarcinomas (Bjorkqvist et al. 1998). In squamous cell carcinoma, the most frequent gain was found at chromosome 3q (Bjorkqvist et al. 1998), specifically at 3q26 (Massion et al. 2002); other common CNV gains were found at chromosomes 8q, 5p and 7p (Bjorkqvist et al. 1998). Losses in 3p were also more common in squamous cell carcinoma than adenocarcinoma (Feder et al. 1998). In adenocarcinoma, the most common documented CNV was a gain at chromosome 7p (Feder et al. 1998). Gains in squamous cell carcinoma were often found in genes GLUT2, THRB, PIK3CA and BCL6, and losses in FHIT, EG9F2 and CACNAID. Interestingly, CNV gains affecting PIK3CA were correlated with increased activity of PKB in squamous cell carcinoma (Massion et al. 2002). A review by Knuutila et al (1999) summarizes DNA copy number losses found in 73 human tumour types, with results separated by chromosome number.
Loss of heterozygosity is also a common occurrence in cancer. Preneoplastic lesions from seven NSCLC tumours were histologically categorized and genetically analyzed. Consistent with above studies that revealed CNV losses at chromosome 3p, loss of heterozygosity was also common at the 3p locus. Percentages of 3p loss of heterozygosity increased from hyperplastic lesions (76%) to dysplastic lesions (86%) to carcinoma in situ (100%). Overall, cumulative loss of heterozygosity was nearly doubled in carcinoma in situ and invasive carcinoma lesions relative to preneoplastic hyperplasia and dysplasia lesions (Hung et al. 1995).
Other studies have revealed a link between gene rearrangements and cancer. Truncated tumour suppressor genes TP53, BRCA1 and BRAC2 have been reported in prostate cancer (Mao et al. 2011). In lung cancer, the gene ALK has been observed to undergo rearrangements, often in the form of gene fusions with EML4 (Sanders and Albitar 2010; Sasaki et al. 2010). These ALK rearrangements often result in increased activity of ALK, higher activation of PI3K-AKT pathways, and ultimately an increased risk of tumourigenesis (Sanders and Albitar 2010). Another common example of a gene fusion is the Philadelphia chromosome, which is formed by a translocation between chromosome 9 and 22 and results in the fusion of BCR and ABL genes. The resulting BCR/ABL gene fusion product was found to be the cause of chronic myelogenous leukemia (reviewed by (Trask 2002). This fusion may be induced by stressors such as ionizing radiation; exposure of human leukemic promyelocytic cells (HL-60) to 5 Gy of gamma-ray radiation resulted in homologous BCR and ABL genes in closer proximity to each other and to the centre of the nucleus (Bartova et al. 2000).
Several rearrangements have also been significantly associated with lung cancer. A balanced translocation at chromosome 19 that results in overexpression of Notch3 in lung epithelial cells has been identified in a number of NSCLC lung cancer cell lines and tumours. This is significant, as Notch3 is not normally expressed in the cells of the lungs (Dang et al. 2000). In fact, transgenic mice engineered to overexpress Notch3 in the lung epithelium died at birth. Analysis of these embryos at embryonic day 18.5 revealed tissue abnormalities in locations where Notch3 mRNA was found, which suggests that overexpression of Notch3 in the lungs may play a role in lung tumourigenesis (Dang et al. 2003). Significant associations have been found between rearrangements in chromosome Xp and higher NSCLC tumour stage, as well as rearrangements in 17p and lower NSCLC tumour stage; 3p and 6q rearrangements were linked with better NSCLC survival (Feder et al. 1998).
CAs that affect pathways controlling cellular growth and apoptosis may promote the development of cancer. In some cases, CAs may alter the activity of proto-oncogenes or tumour suppressor genes (Mitelman et al. 1997; Albertson et al. 2003). Proto-oncogene regulation may be modified such that its gene product is overexpressed; alternatively, the product of the proto-oncogene itself may be affected, producing an abnormally-functioning protein. CAs that affect tumour suppressor genes may inactivate its expression; deletion of the chromosome housing the tumour suppressor gene(s) or unbalanced structural rearrangements may also prevent the expression of tumour suppressor genes (Mitelman et al. 1997). If these alterations enhance cell growth and/or inhibit apoptosis, the cell may become excessively proliferative and unresponsive to external environmental signals (Albertson et al. 2003). There are several pathways that could conceivably be pushed towards malignant transformation by the formation of CAs, including signalling pathways AKT-PI3K-mTOR and RAS-REF-MEK. If a CA occurs within gene(s) related to either of these pathways such that the activity is augmented, this may contribute to the development of a tumour (Sanders and Albitar 2010).
Other factors that may also contribute to increasing the CAs in a tumour include aberrant centromeres and telomerase deficiencies. In some cases, centromeres may become abnormally large due to aberrant amplification. These large centromeres may no longer separate the chromosomes appropriately during cell division, increasing the CA burden in the resulting daughter cells. In telomerase-deficient tumour cells that are proliferating but not being monitored closely, the telomeres may become abnormally short. This becomes an issue for cells that continue dividing because the chromosomes may become damaged during cell division, resulting in chromosomal fusions and breakages. Ultimately, this would also increase the CAs in the daughter cells (Albertson et al. 2003).
Ionizing radiation may also play a role in carcinogenesis. A series of studies focussed on irradiating human papillomavirus (HPV18)-immortalized human bronchial epithelial cells and transplanting the cells into nude mice. The transplantation of these irradiated cells resulted in tumour induction, an effect that was not found when unirradiated cells were transplanted into the mice (Hei et al. 1994). From these tumours, 6 different tumour cell lines were established and analyzed for cytogenetics. All of the lines were found to have CAs, and all harboured losses in genetic information (Weaver et al. 1997). Establishment of further tumour cell lines and their subsequent genetic analysis confirmed that there were CAs, especially in the form of deletions, that were common among the different tumour cell lines (Weaver et al. 2000).
Whether the CA is spontaneous or inherited may also be an important factor in the development of cancer. Non-clonal CAs, which are acquired spontaneously, promote genetic instability and are thought to confer a growth advantage. Ionizing radiation and carcinogens are two stressors that are thought to push the cell towards production of non-clonal CAs, which dominate during the pre-crisis stage of tumour development. After the tumour cells have passed the crisis stage and become immortal, clonal CAs (which are stable, inherited and recurrent in the cell population) dominate the CA landscape of the tumour. Clonal CAs are thought to confer a survival advantage to the cells. Overall, it is suggested that the shifting of equilibrium between non-clonal and clonal CAs is key in the initiation and progression of cancers (Heng, Stevens, et al. 2006; Heng, Bremer, et al. 2006). Interestingly, non-clonal CAs are affected by genotype. In both mouse embryonic stem cells and cultured lymphocytes that were lacking ATM, the spontaneous frequency of non-clonal CAs were significantly increased relative to wild-type cells; the same pattern was also observed in p53-/- cells from a human lung cancer cell line and an ovarian carcinoma cell line (Heng, Stevens, et al. 2006).
Uncertainties and Inconsistencies
Uncertainties and inconsistencies in this KER are as follows:
- 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).
- 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).
- 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).
Known modulating factors
Some studies have documented modulating factors that affect CAs in lung cancer, including age, ethnicity (Lloyd et al. 2013), smoking (Feder et al. 1998; Paik et al. 2012; Lloyd et al. 2013; Minina et al. 2017), sex (Feder et al. 1998), and genotype (Kim et al. 2012; Minina et al. 2017). In NSCLC patients, ALK and EML4 rearrangements have reportedly been influenced by confounding variables such as age (Shaw et al. 2009; Wong et al. 2009; Sasaki et al. 2010), sex (Shaw et al. 2009), and smoking history (Koivunen et al. 2008; Shaw et al. 2009; Wong et al. 2009; Sasaki et al. 2010).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The domain of applicability applies to mammals such as mice, rats, hamsters and humans.
Al-Zoughool, M. & D. Krewski (2009), "Health effects of radon: A review of the literature.", Int. J. Radiat. Biol., 85(1):57–69. doi:10.1080/09553000802635054.
Albertson, D.G. et al. (2003), "Chromosome aberrations in solid tumors.", Nature Genetics. 34(4):369-76. doi:10.1038/ng1215.
Balsara, B.R., J.R. Testa & J.M. Siegfried (1997), "Comparative genomic hybridization analysis detects frequent, often high-level overrepresentation of DNA sequences at 3q, 5p, 7p, and 8q in human non-small cell lung carcinomas", Cancer Research, 57(11):2116-20.
Bartova, E. et al. (2000), "The influence of the cell cycle, differentiation and irradiation on the nuclear location of the abl, bcr and c-myc genes in human leukemic cells.", Leukemia Research, 24(3):233-41, doi: 10.1016/S0145-2126(99)00174-5.
Bjorkqvist, A. et al. (1998), "DNA Gains in 3q Occur Frequently in Squamous Cell Carcinoma of the Lung, But Not in Adenocarcinoma.", Genes Chromosomes and Cancer, 22(1):79-82, doi: 10.1002/(SICI)1098-2264(199805)22:13.3.CO;2-6.
Boffetta, P. et al. (2007), "Original Contribution Chromosomal Aberrations and Cancer Risk: Results of a Cohort Study from Central Europe.", American Journal of Epidemiology, 165(1):36–43, doi:10.1093/aje/kwj367.
Bonassi, S. et al. (2000), "Chromosomal Aberrations in Lymphocytes Predict Human Cancer Independently of Exposure to Carcinogens. European study group on Cytogenetic Biomarkers and Health", Cancer Research, 60(6):1619–1625.
Bonassi, S. et al. (2008), "Chromosomal aberration frequency in lymphocytes predicts the risk of cancer: results from a pooled cohort study of 22,358 subjects in 11 countries.", Carcinogenesis, 29(6):1178–1183. doi:10.1093/carcin/bgn075.
Brooks, A.L. et al. (1995), "The Role of Dose Rate in the Induction of Micronuclei in Deep-Lung Fibroblasts In Vivo after Exposure to Cobalt-60 Gamma Rays The Role of Dose Rate in the Induction of Micronuclei in Deep-L Fibroblasts In Vivo after Exposure to Cobalt-60 Gamma Ray.", Radiat. Res, 144(1):114-8, doi:10.2307/3579244.
Danesi, R. et al. (2003), "Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer." 55(1):57-103. doi:10.1124/pr.18.104.22.168.
Dang, T.P. et al. (2003), "Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice.", Oncogene, 22(13):1988–1997, doi:10.1038/sj.onc.1206230.
Dang, T.P. et al. (2000), "Chromosome 19 Translocation, Overexpression of Notch3, and Human Lung Cancer.", JNCI Journal of the National Cancer Institute, 92(16):1355–1357, doi: 10.1093/jnci/92.16.1355.
Deshpande, A.A. et al. (1996), "Alpha-Particle-Induced Sister Chromatid Exchange in Normal Human Lung Fibroblasts: Evidence for an Extranuclear Target.", Radiation Research, 145(3):260-267, doi: 10.2307/3578980.
El-Zein, R.A. et al. (2017), "Identification of Small and Non-Small Cell Lung Cancer Markers in Peripheral Blood Using Cytokinesis-Blocked Micronucleus and Spectral Karyotyping Assays.", Cytogenet. Genome Res., 152(3):122–131, doi:10.1159/000479809.
El-Zein, R.A. et al. (2014), "The Cytokinesis-Blocked Micronucleus Assay as a Strong Predictor of Lung Cancer: Extension of a Lung Cancer Risk Prediction Model.", Cancer Epidemiol. Biomarkers Prev. 23(11):2462–2470, doi:10.1158/1055-9965.EPI-14-0462.
Feder, M. et al. (1998), "Clinical Relevance of Chromosome Abnormalities in Non-Small Cell Lung Cancer.", Cancer Genetics and Cytogenetics, 102(1):25-31, doi: 10.1016/S0165-4608(97)00274-4.
Genetic Alliance (2010), "Understanding Genetics: A District of Columbia Guide for Patients and Health Professionals", Pub. Med. - NCBI. Genet Alliance Monogr Guid. https://www.ncbi.nlm.nih.gov/pubmed/23586106.
Girard, L. et al. (2000), "Genome-wide Allelotyping of Lung Cancer Identifies New Regions of Allelic Loss, Differences between Small Cell Lung Cancer and Non-Small Cell Lung Cancer, and Loci Clustering", Cancer Res., 60(17):4894-4906.
Hagmar, L. et al. (2004), "Impact of Types of Lymphocyte Chromosomal Aberrations on Human Cancer Risk: Results from Nordic and Italian Cohorts.", Cancer Research, 64(6):2258-63, doi:10.1158/0008-5472.CAN-03-3360.
Hei, T.K et al. (1994), "Malignant transformatin of human bronchial epithelial cells by radon-simulated α-particles.", Carcinogenesis 15(3):431-437, doi: 10.1093/carcin/15.3.431.
Heng, H.H. et al. (2006), "Cancer Progression by Non-Clonal Chromosome Aberrations.", J. Cell. Biochem., 98(6):1424-1435, doi:10.1002/jcb.20964.
Heng, H.H. et al. (2006), "Stochastic Cancer Progression Driven by Non-Clonal Chromosome Aberrations.", J. Cell. Physiol., 208(2):461-472, doi:10.1002/jcp.
Hung, J. et al. (1995), "Allele-Specific Chromosome 3p Deletions Occur at an Early Stage in the Pathogenesis of Lung Carcinoma.", JAMA: The Journal of the American Medical Association, 273(7):558, doi: 10.1001/jama.1995.03520310056030.
Jostes, R.F. (1996), "Genetic, cytogenetic, and carcinogenic effects of radon: a review.", Mutat. Res. / Rev. in Genet. Toxicol. 340(2-3):125–139. doi: 10.1016/s0165-1110(96)90044-5.
Khan, M.A. et al. (1995), "Inhaled radon-induced genotoxicity in Wistar rat, Syrian hamster, and Chinese hamster deep-lung fibroblasts in vivo.", Mutat. Res., 334(2):131–137.
Kim, H.R. et al. (2012), "Distinct Clinical Features and Outcomes in Never-Smokers With Nonsmall Cell Lung Cancer Who Harbor EGFR or KRAS Mutations or ALK Rearrangement.", Cancer, 118(3):729–739, doi:10.1002/cncr.26311.
Knuutila, S. et al. (1999), "DNA Copy Number Losses in Human Neoplasms.", American Journal Of Pathology, 155(3):683-94, doi: 10.1016/S0002-9440(10)65166-8.
Koivunen, J.P. et al. (2008), "Cancer Therapy: Preclinical EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer.", 14(13):4275–4284, doi:10.1158/1078-0432.CCR-08-0168.
Kuramochi, M. et al. (2001), "TSLC1 is a tumor-suppressor gene in human non-small- cell lung cancer.", Nature Genetics, 27(4):427-30, doi: 10.1038/86934.
Liu, B. et al. (2013), "Computational methods for detecting copy number variations in cancer genome using next generation sequencing: principles and challenges.", Oncotarget, 4(11):1868-1881, doi:10.18632/oncotarget.153.
Lloyd, S.M. et al. (2013), "Cytokinesis-Blocked Micronucleus Cytome Assay and Spectral Karyotyping as Methods for Identifying Chromosome Damage in a Lung Cancer Case-Control Population.", Genes Chromosomes Cancer, 52(7):694-707, doi:10.1002/gcc.
Mao, X. et al. (2011), "Chromosome rearrangement associated inactivation of tumour suppressor genes in prostate cancer.", American Journal of Cancer Research. 1(5):604-17.
Massion, P.P. & D.P. Carbone (2003), "The molecular basis of lung cancer: molecular abnormalities and therapeutic implications.", Respiratory Research, 4(1):12, doi: 10.1186/1465-9921-4-12.
Massion, P.P. et al. (2002), "Genomic Copy Number Analysis of Non-small Cell Lung Cancer Using Array Comparative Genomic Hybridization: Implications of the Phosphatidylinositol 3-Kinase Pathway", Cancer Res. 62(13):3636-40.
Miller, R.C. et al. (1996), "The Biological Effectiveness of Radon-Progeny Alpha Particles V . Comparison of Oncogenic Transformation by Accelerator-Produced Monoenergetic Alpha Particles and by Polyenergetic Alpha Particles from Radon Progeny.", Radiat Res., 146(1):75-80. doi: 10.2307/3579398.
Minina, V.I. et al. (2017), "Polymorphisms of GSTM1, GSTT1, GSTP1 genes and chromosomal aberrations in lung cancer patients.", J. Cancer Res. Clin. Oncol, 143(11):2235–2243, doi:10.1007/s00432-017-2486-3.
Mitelman, F., F. Mertens & B. Johansson (1997), "A breakpoint map of recurrent chromosomal rearrangements in human neoplasia.", Nat. Genet., 15 Spec. No.:417-474.
Monchaux, G. et al. (1994), "Carcinogenic and Cocarcinogenic Effects of Radon and Radon Daughters in Rats.", Environmental Health Perspectives, 102(1):64-73, doi: 10.1289/ehp.9410264
Mukherjee, S. et al. (2016), "Chromosomal microarray provides enhanced targetable gene aberration detection when paired with next generation sequencing panel in profiling lung and colorectal tumors.", Cancer Genet., 209(4):119–129, doi:10.1016/j.cancergen.2015.12.011.
Nagasawa, H. et al. (1990), "Cytogenetic effects of extremely low doses of plutonium-238 alpha-particle irradiation in CHO K-1 cells.", Mutat. Research, 244(3):233-8, doi: 10.1016/0165-7992(90)90134-6.
Norppa, H. et al. (2006), "Chromosomal aberrations and SCEs as biomarkers of cancer risk.", Mutat. Res., 600(1-2):37–45, doi:10.1016/j.mrfmmm.2006.05.030.
Ohshima, K. et al. (2017), "Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors.", Sci. Rep., 7(1):641, doi:10.1038/s41598-017-00219-3.
Paik, P.K. et al. (2012), "Driver Mutations Determine Survival in Smokers and never-smokers with stage IIIB/IV lung adenocarcinomas.", Cancer, 118(23):5840-5847, doi:10.1002/cncr.27637.
Pear, W.S. et al. (1998), "Efficient and Rapid Induction of a Chronic Myelogenous Leukemia-Like Myeloproliferative Disease in Mice Receiving P210 bcr/abl-Transduced Bone Marrow.", Blood, 92(10):3780-92.
Petersen, I. et al. (1997), "Advances in Brief Patterns of Chromosomal Imbalances in Adenocarcinoma and Squamous Cell Carcinoma of the Lung.", Cancer Res, 57(12):2331-2335.
Robertson, A. et al. (2013), "The Cellular and Molecular Carcinogenic Effects of Radon Exposure: A Review.", Int. J. Mol. Sci., doi: 10.3390/ijms140714024.
Robertson, J.B. et al. (1983), "Oncogenic Transformation of Mouse BALB/3T3 Cells by Plutonium-238 Alpha Particles.", Radiation Research, 96(2):261-74, doi: 10.2307/3576209.
Roscoe, R.J. et al. (1989), "Lung Cancer Mortality Among Nonsmoking Uranium Miners Exposed to Radon Daughters.", JAMA The Journal of the American Medical Association, 262(5):629-33, doi: 10.1001/jama.262.5.629.
Sanders, H.R. & M. Albitar (2010), "Somatic mutations of signaling genes in non-small-cell lung cancer.", Cancer Genet Cytogenet. 203(1):7–15. doi:10.1016/j.cancergencyto.2010.07.134.
Sasaki, T. et al. (2010), "The Biology and Treatment of EML4-ALK Non-Small Cell Lung Cancer.", Eur. J. Cancer, 46(10):1773–1780. doi:10.1016/j.ejca.2010.04.002.The.
Shaw, A.T. et al. (2009), "Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Who Harbor EML4-ALK.", J. Clin. Oncol., 27(26):4247–4253, doi:10.1200/JCO.2009.22.6993.
Shlien, A. & D. Malkin (2009), "Copy number variations and cancer.", Genome Medicine, 1(6):62, doi:10.1186/gm62.
Smerhovsky, Z. et al. (2001), "Risk of Cancer in an Occupationally Exposed Cohort with Increased Level of Chromosomal Aberrations. Environmental Health Perspectives.", Environ. Health Perspect., 109(1):41-5, doi: 10.1289/ehp.0110941.
Smerhovsky, Z. et al. (2002), "Increased risk of cancer in radon-exposed miners with elevated frequency of chromosomal aberrations.", Mutat. Res., 514(1-2):165-76, doi: 10.1016/S1383-5718(01)00328-X.
Stevens, D.L. et al. (2014), "The Influence of Dose Rate on the Induction of Chromosome Aberrations and Gene Mutation after Exposure of Plateau Phase V79-4 Cells with High-LET Alpha Particles.", Radiat. Res., 182(3):331–337, doi:10.1667/RR13746.1.
Thibervile, L. et al. (1995), "Advances in Brief Evidence of Cumulative Gene Losses with Progression of Premalignant Epithelial Lesions to Carcinoma of the Bronchus.", Cancer Research, 55(22):5133-5139.
Tirmarchel, M. et al. (1993), "Mortality of a cohort of French uranium miners exposed to relatively low radon concentrations.", British Journal of Cancer, 67(5):1090-7. doi: 10.1038/bjc.1993.200.
To, M.D. et al. (2011), "Progressive Genomic Instability in the FVB / Kras LA2 Mouse Model of Lung Cancer.", Molecular Cancer Research, 9(10):1339-45, doi:10.1158/1541-7786.MCR-11-0219.
Trask, B.J. (2002), "Human cytogenetics: 46 Chromosomes, 46 years and counting.", Nature Reviews Genetics, 3(10):769-78, doi:10.1038/nrg905.
Vacquier, B. et al. (2008), "Mortality risk in the French cohort of uranium miners: extended follow-up 1946–1999.", Occup. Environ. Med., 65(9):597–604, doi:10.1136/oem.2007.034959.
Vodenkova, S. et al. (2015), "Structural chromosomal aberrations as potential risk markers in incident cancer patients.", Mutagenesis, 30(4):557–563, doi:10.1093/mutage/gev018.
Vogelstein, B. & K.W. Kinzler (2004), "Cancer genes and the pathways they control.", Nat. Med, 10(8):789–799. doi:10.1038/nm1087.
Walsh, L. et al. (2010), "Radon And The Risk of Cancer Mortality - International Poisson Models For The German Uranium Miners Cohort.", Health Phys., 99(3):292-300, doi:10.1097/HP.0b013e3181cd669d.
Weaver, D.A. et al. (2000), "Localization of tumor suppressor gene candidates by cytogenetic and short tandem repeat analyses in tumorigenic human bronchial epithelial cells.", Carcinogenesis 21(2):205-211, doi:10.1093/carcin/21.2.205.
Weaver, D.A. et al. (1997), "Cytogenetic and molecular genetic analysis of tumorigenic human bronchial epithelial cells induced by radon alpha particles.", Carcinogenesis. 18(6):1251-1257
Werner, A.E., Y. Wang & P.W. Doetsch (2017), "A Single Exposure to Low- or High-LET Radiation Induces Persistent Genomic Damage in Mouse Epithelial Cells In Vitro and in Lung Tissue", Radiat. Res., 188(4):373–380, doi:10.1667/RR14685.1.
Wistuba, I.I. et al. (1999), "Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma.", Oncogene, 18(3):643-50, doi: 10.1038/sj.onc.1202349.
Wong, D.W. et al. (2009), "The EML4-ALK Fusion Gene Is Involved in Various Histologic Types of Lung Cancers From Nonsmokers With Wild-type EGFR and KRAS.", Cancer, 115(8):1723-1733, doi:10.1002/cncr.24181.
Wrage, M. et al. (2009), "Human Cancer Biology Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion.", Clin. Cancer Res., 15(5):1566–1575, doi:10.1158/1078-0432.CCR-08-2188.
Yamada, Y. et al. (2017), "Effect of Age at Exposure on the Incidence of Lung and Mammary Cancer after Thoracic X-Ray Irradiation in Wistar Rats.", Radiat. Res., 187(2):210–220, doi:10.1667/RR14478.1.
Yamada, Y. et al. (2002), "Induction Of Micronuclei In A Rat Alveolar Epithelia Cell Line By Alpha Particle Irradiation.", 99:219–222.
Zabarovsky, E.R., M.I. Lerman & J.D. Minna (2002), "Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers.", Oncogene, 21(45):6915-6935, doi:10.1038/sj.onc.1205835.
Zhang, N. et al. (2016), "Biochimica et Biophysica Acta Classi fi cation of cancers based on copy number variation landscapes.", BBA - Gen. Subj., 1860(11):2750-2755, doi:10.1016/j.bbagen.2016.06.003.