Spatiotemporally resolved colorectal oncogenesis in mini-colons ex vivo.

Three-dimensional organoid culture technologies have revolutionized cancer research by allowing for more realistic and scalable reproductions of both tumour and microenvironmental structures1-3. This has enabled better modelling of low-complexity cancer cell behaviours that occur over relatively short periods of time4. However, available organoid systems do not capture the intricate evolutionary process of cancer development in terms of tissue architecture, cell diversity, homeostasis and lifespan. As a consequence, oncogenesis and tumour formation studies are not possible in vitro and instead require the extensive use of animal models, which provide limited spatiotemporal resolution of cellular dynamics and come at a considerable cost in terms of resources and animal lives. Here we developed topobiologically complex mini-colons that are able to undergo tumorigenesis ex vivo by integrating microfabrication, optogenetic and tissue engineering approaches. With this system, tumorigenic transformation can be spatiotemporally controlled by directing oncogenic activation through blue-light exposure, and emergent colon tumours can be tracked in real-time at the single-cell resolution for several weeks without breaking the culture. These induced mini-colons display rich intratumoural and intertumoural diversity and recapitulate key pathophysiological hallmarks displayed by colorectal tumours in vivo. By fine-tuning cell-intrinsic and cell-extrinsic parameters, mini-colons can be used to identify tumorigenic determinants and pharmacological opportunities. As a whole, our study paves the way for cancer initiation research outside living organisms.

Ultraviolet radiation shapes dendritic cell leukaemia transformation in the skin.

Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues1-4. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)-an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin5. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.

AMPK Phosphorylates ZDHHC13 to Increase MC1R Activity and Suppress Melanomagenesis.

Inherited genetic variations in the melanocortin-1 receptor (MC1R) responsible for human red hair color (RHC) variants are associated with impaired DNA damage repair and increased melanoma risk. MC1R signaling is critically dependent on palmitoylation, primarily mediated by the protein acyltransferase zinc finger DHHC-type palmitoyltransferase 13 (ZDHHC13). A better understanding of how ZDHHC13 is physiologically activated could help identify approaches to prevent melanomagenesis in redheads. Here, we report that AMP-activated protein kinase (AMPK) phosphorylates ZDHHC13 at S208 to strengthen the interaction between ZDHHC13 and MC1R-RHC, leading to enhanced MC1R palmitoylation in redheads. Consequently, phosphorylation of ZDHHC13 by AMPK increased MC1R-RHC downstream signaling. AMPK activation and MC1R palmitoylation repressed UVB-induced transformation of human melanocytes in vitro and delayed melanomagenesis in vivo in C57BL/6J-MC1R-RHC mice. The importance of AMPK to MC1R signaling was validated in human melanomas where AMPK upregulation correlated with expression of factors downstream from MC1R signaling and with prolonged patient survival. These findings suggest AMPK activation as a promising strategy to reduce melanoma risk, especially for individuals with red hair. SIGNIFICANCE: Phosphorylation of ZDHHC13 by AMPK at S208 promotes MC1R activation and suppresses melanocyte transformation, indicating activation of AMPK as a potential approach to prevent melanoma in people with red hair.

Low-dose but not high-dose γ-irradiation elicits the dominant-negative effect of mutant p53 in vivo.

Contrary to high doses irradiation (HDR), the biological consequences of dose irradiation (LDR) in breast cancer remain unclear due to the complexity of human epidemiological studies. LDR induces DNA damage that activates p53-mediated tumor-suppressing pathways promoting DNA repair, cell death, and growth arrest. Monoallelic p53 mutations are one of the earliest and the most frequent genetic events in many subtypes of cancer including ErbB2 breast cancer. Using MMTV/ErbB2 mutant p53 (R172H) heterozygous mouse model we found differential p53 genotype-specific effect of LDR vs. HDR on mammary tumorigenesis. Following LDR, mutant p53 heterozygous tumor cells exhibit aberrant ATM/DNA-PK signaling with defects in sensing of double-strand DNA brakes and deficient DNA repair. In contrast, HDR-induced genotoxic stress is sufficient to reach the threshold of DNA damage that is necessary for wtp53 induced DNA repair and cell cycle arrest. As a result, mutant p53 endows dominant-negative effect promoting mammary tumorigenesis after low-impact DNA damage leading to the selection of a genetically unstable proliferative population, with negligible mutagenic effect on tumors carrying wtp53 allele.

Quantitative modeling of carcinogenesis induced by single beams or mixtures of space radiations using targeted and non-targeted effects.

Ionizing radiations encountered by astronauts on deep space missions produce biological damage by two main mechanisms: (1) Targeted effects (TE) due to direct traversals of cells by ionizing tracks. (2) Non-targeted effects (NTE) caused by release of signals from directly hit cells. The combination of these mechanisms generates non-linear dose response shapes, which need to be modeled quantitatively to predict health risks from space exploration. Here we used a TE + NTE model to analyze data on APC(1638N/+) mouse tumorigenesis induced by space-relevant doses of protons, 4He, 12C, 16O, 28Si or 56Fe ions, or γ rays. A customized weighted Negative Binomial distribution was used to describe the radiation type- and dose-dependent data variability. This approach allowed detailed quantification of dose-response shapes, NTE- and TE-related model parameters, and radiation quality metrics (relative biological effectiveness, RBE, and radiation effects ratio, RER, relative to γ rays) for each radiation type. Based on the modeled responses for each radiation type, we predicted the tumor yield for a Mars-mission-relevant mixture of these radiations, using the recently-developed incremental effect additivity (IEA) synergy theory. The proposed modeling approach can enhance current knowledge about quantification of space radiation quality effects, dose response shapes, and ultimately the health risks for astronauts.

Radiation-Induced Phosphorylation of a Prion-Like Domain Regulates Transformation by FUS-CHOP.

Chromosomal translocations generate oncogenic fusion proteins in approximately one-third of sarcomas, but how these proteins promote tumorigenesis is not well understood. Interestingly, some translocation-driven cancers exhibit dramatic clinical responses to therapy, such as radiotherapy, although the precise mechanism has not been elucidated. Here we reveal a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance that also explains the remarkable sensitivity of myxoid liposarcomas to radiation therapy. FUS-CHOP interacted with chromatin remodeling complexes to regulate sarcoma cell proliferation. One of these chromatin remodelers, SNF2H, colocalized with FUS-CHOP genome-wide at active enhancers. Following ionizing radiation, DNA damage response kinases phosphorylated the prion-like domain of FUS-CHOP to impede these protein-protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupted oncogenic targeting of chromatin remodelers required for FUS-CHOP-driven sarcomagenesis. This mechanism of disruption links phosphorylation of the prion-like domain of an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma. SIGNIFICANCE: Prion-like domains, which are frequently translocated in cancers as oncogenic fusion proteins that drive global epigenetic changes, confer sensitivity to radiation via disruption of oncogenic interactions.

NF1 mutation drives neuronal activity-dependent initiation of optic glioma.

Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising  the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.

Modeling Radiation-Induced Neoplastic Cell Transformation In Vitro and Tumor Induction In Vivo with the Local Effect Model.

Ionizing radiation induces DNA damage to cycling cells which, if left unrepaired or misrepaired, can cause cell inactivation or heritable, viable mutations. The latter can lead to cell transformation, which is thought to be an initial step of cancer formation. Consequently, the study of radiation-induced cell transformation promises to offer insights into the general properties of radiation carcinogenesis. As for other end points, the effectiveness in inducing cell transformation is elevated for radiation qualities with high linear energy transfer (LET), and the same is true for cancer induction. In considering DNA damage as a common cause of both cell death and transformations, a worthwhile approach is to apply mathematical models for the relative biological effectiveness (RBE) of cell killing to also assess the carcinogenic potential of high-LET radiation. In this work we used an established RBE model for cell survival and clinical end points, the local effect model (LEM), to estimate the transformation probability and the carcinogenic potential of ion radiation. The provided method consists of accounting for the competing processes of cell inactivation and induction of transformations or carcinogenic events after radiation exposure by a dual use of the LEM. Correlations between both processes inferred by the number of particle impacts to individual cells were considered by summing over the distribution of hits that individual cells receive. RBE values for cell transformation in vitro were simulated for three independent data sets, which were also used to gauge the approach. The simulations reflect the general RBE systematics both in magnitude and in energy and LET dependence. To challenge the developed method, in vivo carcinogenesis was investigated using the same concepts, where the probability for cancer induction within an irradiated organ was derived from the probability of finding carcinogenic events in individual cells. The predictions were compared with experimental data of carcinogenesis in Harderian glands of mice. Again, the developed method shows the same characteristics as the experimental data. We conclude that the presented method is helpful to predictively assess RBE for both neoplastic cell transformation and tumor induction after ion exposure within a wide range of LET values. The theoretical concept requires a non-linear component in the photon dose response for carcinogenic end points as a precondition for the observed enhanced effects after ion exposure, thus contributing to a long debate in epidemiology. Future work will use the method for assessing cancer induction in radiation therapy and exposure scenarios frequently discussed in radiation protection.

Cellular Senescence and the Senescence-Associated Secretory Phenotype as Drivers of Skin Photoaging.

Chronic exposure to UVR is known to disrupt tissue homeostasis, accelerate the onset of age-related phenotypes, and increase the risk for skin cancer-a phenomenon defined as photoaging. In this paper, we review the current knowledge on how UV exposure causes cells to prematurely enter cellular senescence. We describe the mechanisms contributing to the accumulation of senescent cells in the skin and how the persistence of cellular senescence can promote impaired regenerative capacity, chronic inflammation, and tumorigenesis associated with photoaging. We conclude by highlighting the potential of senolytic drugs in delaying the onset and progression of age-associated phenotypes in the skin.

Actinic Keratoses: Reconciling the Biology of Field Cancerization with Treatment Paradigms.

This Perspective briefly reviews the relationship between UV-induced mutations in habitually sun-exposed human skin and subsequent development of actinic keratoses (AKs) and skin cancers. It argues that field therapy rather than AK-selective therapy is the more logical approach to cancer prevention and hypothesizes that treatment early in the process of field cancerization, even prior to the appearance of AKs, may be more effective in preventing cancer as well as more beneficial for and better tolerated by at-risk individuals. Finally, the Perspective encourages use of rapidly advancing DNA analysis techniques to quantify mutational burden in sun-damaged skin and its reduction by various therapies.

Long-term 1800MHz electromagnetic radiation did not induce Balb/c-3T3 cells malignant transformation.

There is an increased public concern about potential health hazards of exposure to electromagnetic radiation (EMR). To declare the carcinogenic effects of 1800 MHz EMR. In this study, Balb/c-3T3 cells were exposed to 1800 MHz EMR for 80 days. The cells were harvested for cell proliferation detection, cell cycle assay, plate clone, and soft agar formation assay, transwell assay, and mRNA microarray detection. 1800 MHz EMR promoted Balb/c-3T3 proliferation. No clones were observed in both plate clone and soft agar clone formation assay. The percentage of cells in S phase in Balb/c-3T3 cells of 80d Expo was obviously higher than the percetage in 80d Sham cells. 80d Expo Balb/c-3T3 cells had stronger migration ability than Sham cells. The mRNA microarray results indicated that cell cycle, cell division, and DNA replication were the main biological processes the significant genes enriched, with higher expression of RPs and Mcms. 1800 MHz EMR promoted Balb/c-3T3 cells proliferation and migration. The mRNA microarray results indicated that cell cycle, cell division, and DNA replication were the main biological processes the significant genes enriched.

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

Protection from Ultraviolet Damage and Photocarcinogenesis by Vitamin D Compounds.

Exposure of skin cells to UV radiation results in DNA damage, which if inadequately repaired, may cause mutations. UV-induced DNA damage and reactive oxygen and nitrogen species also cause local and systemic suppression of the adaptive immune system. Together, these changes underpin the development of skin tumours. The hormone derived from vitamin D, calcitriol (1,25-dihydroxyvitamin D3) and other related compounds, working via the vitamin D receptor and at least in part through endoplasmic reticulum protein 57 (ERp57), reduce cyclobutane pyrimidine dimers and oxidative DNA damage in keratinocytes and other skin cell types after UV. Calcitriol and related compounds enhance DNA repair in keratinocytes, in part through decreased reactive oxygen species, increased p53 expression and/or activation, increased repair proteins and increased energy availability in the cell when calcitriol is present after UV exposure. There is mitochondrial damage in keratinocytes after UV. In the presence of calcitriol, but not vehicle, glycolysis is increased after UV, along with increased energy-conserving autophagy and changes consistent with enhanced mitophagy. Reduced DNA damage and reduced ROS/RNS should help reduce UV-induced immune suppression. Reduced UV immune suppression is observed after topical treatment with calcitriol and related compounds in hairless mice. These protective effects of calcitriol and related compounds presumably contribute to the observed reduction in skin tumour formation in mice after chronic exposure to UV followed by topical post-irradiation treatment with calcitriol and some, though not all, related compounds.

Treatment of Histologic Transformation.

Histologic transformation from follicular lymphoma to aggressive lymphoma historically had a poor prognosis. Routine use of anti-CD20 antibody rituximab has changed the landscape of follicular lymphoma (FL) such that outcomes are improved in select patients, similar to de-novo diffuse large B-cell lymphoma. Several biological and clinical biomarkers can predict risk of transformation, and ongoing research is improving understanding of the biology surrounding the transformation process. This review provides an overview of risk factors, prognosis, and treatment of histologic transformation of FL.

Simulating galactic cosmic ray effects: Synergy modeling of murine tumor prevalence after exposure to two one-ion beams in rapid sequence.

Health risks from galactic cosmic rays (GCR) in space travel above low earth orbit remain a concern. For many years accelerator experiments investigating space radiation induced prevalence of murine Harderian gland (HG) tumorigenesis have been performed to help estimate GCR risks. Most studies used acute, relatively low fluence, exposures. Results on a broad spectrum of individual ions and linear energy transfers (LETs) have become available. However, in space, the crew are exposed simultaneously to many different GCR. Recent upgrades at the Brookhaven NASA Space Radiation Laboratory (NSRL) now allow mixtures in the form of different one-ion beams delivered in rapid sequence. This paper uses the results of three two-ion mixture experiments to illustrate conceptual, mathematical, computational, and statistical aspects of synergy analyses and also acts as an interim report on the mixture experiments' results. The results were interpreted using the following: (a) accumulated data from HG one-ion accelerator experiments; (b) incremental effect additivity synergy theory rather than simple effect additivity synergy theory; (c) parsimonious models for one-ion dose-effect relations; and (d), computer-implemented numerical methods encapsulated in freely available open source customized software. The main conclusions are the following. As yet, the murine HG tumorigenesis experimental studies show synergy in only one case out of three. Moreover, some theoretical arguments suggest GCR-simulating mixed beams are not likely to be synergistic. However, more studies relevant to possible synergy are needed by various groups that are studying various endpoints. Especially important is the possibility of synergy among high-LET radiations, since individual high-LET ions have large relative biological effectiveness for many endpoints. Selected terminology, symbols, and abbreviations. DER - dose-effect relation; E(d) - DER of a one-ion beam, where d is dose; HG prevalence p - in this paper, p is the number of mice with at least one Harderian gland tumor divided by the number of mice that are at risk of developing Harderian gland tumors (so that in this paper prevalence p can never, conceptually speaking, be greater than 1); IEA - incremental effect additivity synergy theory; synergy level - a specification, exemplified in Fig. 5, of how clear-cut an observed synergy is; mixmix principle - a consistency condition on a synergy theory which insures that the synergy theory treats mixtures of agent mixtures in a mathematically self-consistent way; NTE - non-targeted effect(s); NSNA - neither synergy nor antagonism; SEA - simple effect additivity synergy theory; TE - targeted effect(s); ß* - ion speed relative to the speed of light, with 0 < ß* < 1; SLI - swift light ion(s).

The ß-Blocker Carvedilol Prevented Ultraviolet-Mediated Damage of Murine Epidermal Cells and 3D Human Reconstructed Skin.

The ß-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but the mechanism is unknown. Since carvedilol possesses antioxidant activity, this study investigated whether carvedilol prevents oxidative photodamage of skin, a precursor event in skin carcinogenesis. The effects of carvedilol, metoprolol (a ß-blocker without antioxidant property), and 4-hydroxycarbazole (4-OHC, a carvedilol synthesis intermediate and a free radical scavenger) were compared on UV- or H2O2-induced cell death and reactive oxygen species (ROS) production in murine epidermal JB6 P+ cells. Although carvedilol attenuated cell death, metoprolol and 4-OHC failed to show protective effects. As expected, increased cellular ROS induced by H2O2 or UV was abolished by carvedilol and 4-OHC, but not by metoprolol. Consistently, carvedilol attenuated the formation of UV-induced cyclobutane pyrimidine dimers (CPDs) and release of prostaglandin E2 in JB6 P+ cells. Carvedilol's activity was further confirmed in full thickness 3D human reconstituted skin, where carvedilol attenuated UV-mediated epidermal thickening, the number of Ki-67 and p53 positive cells as well as CPD formation. Based on pathway-specific Polymerase Chain Reaction (PCR) Array analysis, carvedilol treatment in many cases normalized UV-induced expression changes in DNA repair genes. Thus, carvedilol's photoprotective activity is not attributed to ß-blockade or direct ROS-scavenging capacity, but likely via DNA repair regulation.

Elastic scattering spectroscopy for monitoring skin cancer transformation and therapy in the near infrared window.

There is a pressing need for monitoring cancerous tissue response to laser therapy. In this work, we evaluate the viability of elastic scattering spectroscopy (ESS) to monitor malignant transformations and effects of laser therapy of induced skin cancer in a hamster model. Skin tumors were induced in 35 mice, half of which were irradiated with 980 nm laser diode. Physiological and morphological transformations in the tumor were monitored over a period of 36 weeks using elastic scattering spectroscopy, in the near infrared window. Analytical model for light scattering was used to derive scattering optical properties for both transformed tissue and laser-treated cancer. The tissue scattering over the wavelength range (700-950 nm) decreased remarkably as the carcinogen-induced tissue transformed towards higher stages. Conversely, reduced scattering coefficient noticeably increased with increasing the number of laser irradiation sessions for the treated tumors. The relative changes in elastic scattering signal for transformed tissue were significantly different (p < .05). Elastic scattering signal intensity for laser-treated tissue was also significantly different (p < .05). Reduced scattering coefficient of treated tissue exhibited nearly 80% recovery of its normal skin value at the end of the experiment, and the treatment outcome could be improved by adjusting the number of sessions, which we can predict through spectroscopic optical feedback. This study demonstrates that ESS can quantitatively provide functional information that closely corresponds to the degree of pathologic transformation. ESS may well be a viable technique to optimize systemic melanoma and non-melanoma skin cancer treatment based on noninvasive tumor response.

Transformation of Grade II to Grade III Rhabdoid-Papillary Meningioma: Is Stereotactic Radiosurgery the Culprit? A Case Report and Literature Review.

BACKGROUND: In the management of meningiomas, single-fraction stereotactic radiosurgery (SRS) is an established alternative treatment to surgical resection. However, its effects on tumorigenesis and malignant transformation are still uncertain. CASE DESCRIPTION: We have described a grade II parafalcine meningioma that was initially surgically resected (Simpson 2 clearance) and then managed with a single dose of SRS on recurrence. The tumor recurred again 7 years later, with histological features of a grade III rhabdoid-papillary lesion, with local brain invasion. CONCLUSION: To the best of our knowledge, this is the first report to describe malignant transformation of a grade II to grade III meningioma after SRS to date.

Irradiation induces p53 loss of heterozygosity in breast cancer expressing mutant p53.

Mutations in one allele of the TP53 gene in cancer early stages are frequently followed by the loss of the remaining wild-type allele (LOH) during tumor progression. However, the clinical impact of TP53 mutations and p53LOH, especially in the context of genotoxic modalities, remains unclear. Using MMTV;ErbB2 model carrying a heterozygous R172H p53 mutation, we report a previously unidentified oncogenic activity of mutant p53 (mutp53): the exacerbation of p53LOH after irradiation. We show that wild-type p53 allele is partially transcriptionally competent and enables the maintenance of the genomic integrity under normal conditions in mutp53 heterozygous cells. In heterozygous cells γ-irradiation promotes mutp53 stabilization, which suppresses DNA repair and the cell cycle checkpoint allowing cell cycle progression in the presence of inefficiently repaired DNA, consequently increases genomic instability leading to p53LOH. Hence, in mutp53 heterozygous cells, irradiation facilitates the selective pressure for p53LOH that enhances cancer cell fitness and provides the genetic plasticity for acquiring metastatic properties.

MEAN VALUE OF LET FOR ONCOGENIC EFFECTS OF RADON AND ITS PROGENY.

The topic of the article is to define the average value of linear energy transfer (LET) for carcinogenic effects of radon progeny. The microdosimetric model of boundary specific energy is used. It follows that the effect at high LET should decrease approximately with the third power of LET. This is verified by the analysis of the relationship between radiation effects ratio and LET in published experiments with oncogenic transformation of mammalian cells irradiated with the monoenergetic alpha particles. If these cells are exposed with the radon irradiator, our analysis leads us to conclude that the oncogenic effect of radon progeny is comparable to that of alpha particles with a LET of 75 keV/µm. It is about a quarter lower than the LET value, where the effect of the monoenergetic alpha particles reaches its maximum level. Some implications for lung cancer due to radon inhalation may also be carefully examined.