Abdelhalim, M

Ainsbury, E

Anderson, R

Badie, C

Modarai, B

Moquet, J

Patel, A

Saha, P

Smith, A

Circulation

British Heart Foundation (FS/17/24/32596 to B.M)

Abdelhalim, MA

Brunel University Research Archive

A higher incidence of chromosomal aberrations in operators performing a large volume of endovascular procedures

Abdelhalim, Mohamed

Patel, Ashish

Moquet, Jayne

Saha, Prakash

Smith, Alberto

Badie, Christophe

Anderson, Rhona

Ainsbury, Elizabeth A.

Modarai, Bijan

King's Research Portal

                       King’s Research Portal  Document VersionPeer reviewed versionLink to publication record in King's Research PortalCitation for published version (APA):Abdelhalim, M., Patel, A., Moquet, J., Saha, P., Smith, A., Badie, C., Anderson, R., Ainsbury, E. A., & Modarai,B. (Accepted/In press). A higher incidence of chromosomal aberrations in operators performing a large volumeof endovascular procedures. Circulation.Citing this paperPlease note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this maydiffer from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination,volume/issue, and date of publication details. 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Oct. 2023 1 TITLE PAGE 1  2 Full title 3  4 A higher incidence of chromosomal aberrations in operators performing a large volume of 5 endovascular procedures 6  7  8 Running title (50 characters max): 9  10 Chromosomal aberrations in endovascular operators 11  12  13 Author degrees 14  15 Mohamed Abdelhalim  BSc, MRCS 16 Ashish Patel    PhD, FRCS 17 Jayne Moquet    PhD 18 Prakash Saha    PhD, FRCS 19 Alberto Smith    PhD 20 Christophe Badie   PhD 21 Rhona Anderson   PhD 22 Elizabeth Ainsbury   PhD 23 Bijan Modarai    PhD, FRCS 24  25  26 Summary (120 characters max): 27  28 Higher frequency of radiation-related chromosomal aberrations identified in endovascular 29 operators. 30  31  32 Twitter handles: 33  34 Mohamed Abdelhalim   @ma_abdelhalim 35 Bijan Modarai     @b_modarai 36 KCL (School of CVMS)   @kingscardio 37  38  39 Funding sources 40  41 British Heart Foundation (FS/17/24/32596) to Bijan Modarai. 42  43 Conflict of Interest Disclosures 44  45 Bijan Modarai: Consulting/Advisory board for Cydar Medical; Consulting for Philips; 46 Advisory board, proctoring and speaker’s fees for Cook. 47  48 All other authors: none  49  2 A HIGHER INCIDENCE OF CHROMOSOMAL ABERRATIONS IN OPERATORS PERFORMING A LARGE VOLUME OF ENDOVASCULAR PROCEDURES  Mohamed A Abdelhalim (MBChB, MRCS)1, Ashish Patel (PhD, FRCS)1, Jayne Moquet (PhD)2, Prakash Saha (PhD)1, Alberto Smith (PhD)1, Christophe Badie (PhD)2, Rhona Anderson (PhD)3, Elizabeth Ainsbury (PhD)2, Bijan Modarai (PhD, FRCS)1*  1Academic Department of Vascular Surgery, School of Cardiovascular Medicine and Sciences, King’s College London, BHF Centre of Excellence at Guy’s and St Thomas’ NHS Foundation Trust, London, UK 2Public Health England Centre for Radiation, Chemical and Environmental Threats and Hazards, Chilton, Oxfordshire, UK. 3Centre for Health Effects of Radiological and Chemical Agents, College of Health, Medicine and Life Sciences, Brunel University London, UK  *Corresponding Author: Professor Bijan Modarai, Academic department of Vascular surgery, 1st Floor St Thomas’ Hospital, King’s College London Email: bijan.modarai@kcl.ac.uk   Cardiovascular interventions using X-ray guidance are increasing in both volume and 1 complexity. The long-term biological effects of chronic low dose radiation exposure in 2 operators performing these procedures are, however, largely unknown.  Occupational 3 safety limits are based on physical dosimetry only and do not consider individual 4 biological sensitivity to radiation. We previously reported DNA damage in lymphocytes 5 isolated from operators performing endovascular aortic repair (EVAR) (1). Expression 6 of -H2AX and phosphorylated ataxia telangiectasia mutated (pATM), which are 7 markers of acute DNA damage/repair, rose immediately after performing EVAR and 8 normalised the following day. These markers, however, do not reflect the effects of 9 chronic exposure, including chromosomal aberrations that may herald genomic 10 instability and predisposition to malignancy. Here we report important findings 11 pertaining to these aberrations in an international group of operators performing a 12 large volume of complex endovascular interventions, including branched and 13 fenestrated EVAR (B/FEVAR). 14  15 Peripheral blood was collected from endovascular operators (n=12, 11 male) and 16 radiation-naïve general surgeons as controls (n=6, 5 male), all of whom gave informed 17 consent. The study was approved by our institutional review committee 18 (Reference:16/LO/1111). The median age of endovascular and control operators [(50 19 (36-55) vs 47 (36-52), respectively, p=0.37] and years in practice [13.5 (3-20) vs 10.5 20 (5-16) respectively, p=0.19] were comparable. There were no inter-group differences 21 in radiation exposures for personal health reasons, smoking history or medications. 22 Two endovascular operators had cancer, a squamous skin and renal lesion, both 23 curatively treated at age 49 and 16, respectively. Endovascular operators performed 24 a median of 35 (20-100) standard EVARs and 70 (30-100) B/FEVARs annually with a 25 median annual personal radiation dose of 0.96mSv (0.22-13.64) in the three years 26 prior to blood sampling. All endovascular operators wore lead gowns and thyroid 27 shields.  Lead leg shields, headcaps and goggles were used by 58%, 42% and 92% 28 of operators, respectively. Two operators used a ceiling suspended radiation 29 protection suit and one used scatter radiation absorbing drapes.  30  31  3 Giemsa-stained metaphase preparations were used to analyse the full complement of 1 chromosomes in at least 3,000 lymphocytes per operator (Figure 1A). Semi-2 automated scoring found a dicentric chromosome frequency of 0.11 (0.03-0.16) per 3 100 cells in the endovascular operators compared with 0.04 (0-0.06) in controls 4 (p=0.002, Figure 1B). There was no correlation between age of operator and dicentric 5 frequency [Pearson coefficient r=0.04 (-0.44 - 0.50, p=0.876)]. 6  7 More than 2,000 lymphocytes from nine operators (5 exposed, 4 control) were 8 analysed by multiplex fluorescence in situ hybridisation (m-FISH) using fluorescent 9 probes hybridised to metaphase chromosomes. The frequency of unstable, complex 10 exchanges which involve three or more breaks in two or more chromosomes (0.48 vs 11 0.24 per 100 cells, Mann-Whitney U test, p=0.32) and stable, reciprocal translocations 12 (0.86 vs 0.59 per 100 cells, Mann-Whitney U test, p=0.38) trended higher in 13 endovascular operators (Figure 1C-F). Stable exchanges can be passed onto 14 subsequent cell generations during mitosis and are, therefore, particularly useful for 15 monitoring cytogenetic effects of chronic radiation exposures. Aneuploidy, which 16 refers to abnormal loss of chromosomes, was more frequent in radiation exposed 17 operators (Wilcoxon Signed Rank test, p=0.004, Figure 1G-H), with a median 18 difference of 0.35 per chromosome. 19  20 Dicentric chromosomes, formed by cleavage and incorrect repair of double-stranded 21 DNA, indicate genomic instability and reflect radiation exposure during the 22 lymphocyte’s lifespan, which is approximately 3 years (2). Their frequency increases 23 proportionally to cumulative radiation exposures (<~5Gy), allowing their use for 24 biological assessment of chronic exposures (2). The dicentric frequencies we 25 observed fall below the threshold that allows reliable inference of effective exposure 26 dose using current nomograms. Nevertheless, we found an almost 3-fold higher 27 incidence of dicentrics in endovascular operators compared with radiation naïve 28 controls. The dicentric count in the latter group was comparable to that of the general 29 population, which is generally quoted as approximately 0.06 per 100 cells (2). Our 30 findings are corroborated by a recent report of higher dicentric frequency in 31 interventional radiologists (3). These data highlight the need to investigate whether 32 partial body irradiation to unshielded areas such as the legs may contribute to this 33 level of chromosomal damage over time (1). 34  35 The chromosomal aberrations detected in the present study using m-FISH, whilst not 36 necessarily caused by occupational radiation exposure, are also associated with 37 cancer (4). These increase the burden of genetic alterations which can cause defects 38 in cell proliferation, induce proteotoxic stress, and promote tumorigenesis, but 39 uncertainties remain around linking these actions to cancer risk. The impact of chronic 40 low dose occupational radiation exposure on the health of medical workers is uncertain 41 and requires extensive epidemiological and mechanistic studies to inform (5). Our 42 exploratory findings are hypothesis generating and strengthen the case for larger 43 scale prospective studies that accurately record radiation doses to all body parts, 44 capture health events, and relate these to cytogenetic markers of chronic exposure. 45  46 Data, materials, and methods will be made available to researchers through direct 47 communication with the corresponding author.48  4 References:  1. El-Sayed T, Patel AS, Cho JS, Kelly JA, Ludwinski FE, Saha P, Lyons OT, Smith A, Modarai B, Guy’s and St Thomas’ Cardiovascular Research Collaborative. Radiation-Induced DNA Damage in Operators Performing Endovascular Aortic Repair. Circulation. 2017;136(25):2406-2416. 2. Romm H, Ainsbury E, Barnard S, Barrios L, Barquinero JF, Beinke C, Deperas M, Gregoire E, Koivistoinen A, Lindholm C, et al. Automatic scoring of dicentric chromosomes as a tool in large scale radiation accidents. Mutat Res. 2013;756(1-2):174-183. 3. Lee Y, Lee WJ, Jin YW, Jang S. Interventional radiologists have a higher rate of chromosomal damage due to occupational radiation exposure: a dicentric chromosome assay. Eur Radiol. 2021;31:8256-8263. 4. Bonassi S, Norppa H, Ceppi M, Strömberg U, Vermeulen R, Znaor A, Cebulska-Wasilewska A, Fabianova E, Fucic A, Gundy S, et al. Chromosomal aberration frequency in lymphocytes predicts the risk of cancer: results from a pooled cohort study of 22,358 subjects in 11 countries. Carcinogenesis. 2008;29:1178-1183. 5. Gilbert ES, Little MP, Preston DL, Stram DO. Issues in interpreting epidemiologic studies of populations exposed to low-dose, high-energy photon radiation. J Natl Cancer Inst Monogr. 2020;2020(56):176-187.   Figure 1. Chromosomal aberrations in exposed endovascular operators versus controls. A, Chromosome spread of a lymphocyte in metaphase, visualised by Giemsa staining, showing a dicentric chromosome (red arrow) and an acentric fragment (blue arrow). In this aberration, breaks in two chromosomes followed by incorrect repair have resulted in the formation of a single chromosome containing two centromeres and a chromosome fragment containing no centromeres. B, Frequency of dicentric chromosomes per 100 cells in endovascular operators compared with radiation naïve control operators [0.11 vs 0.04, respectively (*Mann-Whitney U test, p=0.002)]. C, Multiplex fluorescence in situ hybridisation (m-FISH) demonstrating a chromosome spread of 22 pairs of autosomes and single X and Y chromosomes. A simple reciprocal translocation between chromosomes 3 and 8 is highlighted by the yellow arrows. D, An illustration depicting the formation of the reciprocal translocation seen in C, where ionising radiation has caused breaks in chromosomes 3 and 8, which have then been repaired incorrectly such that a fragment of chromosome 8 is attached to chromosome 3 and vice versa. E, A complex, unstable, non-transmissible chromosome rearrangement visualised by m-FISH, with yellow arrows highlighting the chromosomes (1, 8 and 10) affected by breaks and incorrect repair. F, Illustration depicting the formation of the complex rearrangement seen in E, where ionising radiation has caused breaks in three chromosomes followed by incorrect repair. The centromere-containing portion of chromosome 10 has attached to chromosome 8, whilst the acentric portion has attached to chromosome 1. Acentric portions of chromosomes 1 and 8 have also attached to form an acentric fragment. G, A chromosome spread with aneuploidy visualised by m-FISH. Aneuploidy refers to the abnormal loss or gain of chromosomes within the cell. In this instance, the yellow arrows highlight the missing chromosomes 1 and 20. H, Bar chart showing the abnormal loss of each chromosome (aneuploidy) per 100 cells in endovascular operator samples (red) compared with the radiation naive controls (blue) after analysing a total of over 2,000 cells by m-FISH, median of differences 0.35, Wilcoxon Signed Rank test p=0.004.  

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A higher incidence of chromosomal aberrations in operators performing a large volume of endovascular procedures

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