Molecular Detection of ETV6-NTRK3 Gene Fusion in a Sample of Iraqi Breast Cancer Patients
DOI:
https://doi.org/10.14500/aro.12889Keywords:
ETV6-NTRK3 fusion, Fluorescence in situ hybridization, Invasive carcinoma NST, Invasive lobular carcinoma, Secretory breast carcinomaAbstract
—Breast cancer (BC) remains a health challenge in Iraq, with patients presenting at younger ages and advanced stages. While gene fusions, particularly ETV6-NTRK3, are established oncogenic drivers in subtypes like secretory breast carcinoma (SBC), their prevalence within the Iraqi population remains unexplored. This study aimed to detect the ETV6-NTRK3 gene fusion in Iraqi patients with BC to define its diagnostic specificity and clinicopathological correlates. Formalin-fixed paraffin-embedded tissue blocks from 60 women (aged 20–50 years) diagnosed with BC were collected. Samples were classified into three equal groups: SBC, Invasive Carcinoma of no special type, and invasive lobular carcinoma (n = 20 for each). The ETV6-NTRK3 fusion was detected using fluorescence in situ hybridization with a dual-color break-apart probe. The ETV6-NTRK3 fusion was detected exclusively in the SBC, with a prevalence of 100% (19/19 successfully scored cases), while it was absent in all scored cases of other groups, yielding a positive predictive value of 100% and a negative predictive value of 100%. Fusion-positive SBC tumors were associated with clinicopathological features: they were exclusively low to intermediate histological grade (Grades I-II) and predominantly presented at early pathological stages (Stage I-II: 84.2%). The fusion-positive cases were 93 times more likely to present with an early stage of disease compared with fusion-negative cases (odds ratio: 93.33; 95% confidence interval: 16.15–539.19). In conclusion, the ETV6-NTRK3 fusion may be a definitive molecular hallmark of SBC in Iraqi patients, and could demonstrate perfect diagnostic specificity and association with a less aggressive phenotype.
Downloads
References
Abulkhair, O., Omair, A., Makanjuola, D., Al Zaid, M., Al Riyees, L., Abdelhafiez, N., Abdelhafiez, N., Masuadi, E., Alamri, G., Althan, F., Alkushi, A., and Partridge A., 2024. Breast cancer in young women: Is it different? A singlecenter retrospective cohort study. Clinical Medicine Insights: Oncology, 18, pp.1-9.
Al Alwan, N.A., 2022. Cancer control and oncology care in Iraq. Journal of Contemporary Medical Sciences, 8(1), pp.82-85.
Ali, A.N.M., and Muslim, S.N., 2025. Breast cancer in Iraq: A comprehensive review of disease burden, risk factors, and healthcare response. South Asian Research Journal of Biology and Applied Biosciences, 7(6), pp.349-360.
Al-Janaby, M.S., Al-Ani, M.Q., and Lafta, F.M., 2025. Genotypic and phenotypic study of PDCD4 gene concerning microRNA polymorphism in breast cancer. Iraqi Journal of Science, 66(1), pp.77-89.
Alkashaf, K.H., and Mohammed, S.I., 2024. Impact of clinical pharmacist-led interventions on short term quality of life among breast cancer women taking chemotherapy. Iraqi Journal of Pharmaceutical Sciences, 33(4), pp.166-173.
Ammar, K.A., and Altaee, M.F., 2022. Correlation of TMPRSS2-ERG gene fusion status with clinicopathological characteristics in prostate cancer of Iraqi patients. Iraqi Journal of Agricultural Sciences, 53(3), pp.487-495.
Boustros, P., Sanchez, L.M., Gaboury, L., and El Khoury, M., 2024. Secretory carcinoma of the breast: Radiologic-pathologic correlation. Journal of Breast Imaging, 6(5), pp.520-528.
Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R.L., Soerjomataram, I., and Jemal, A., 2024. Global cancer statistics 2022; GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 74(3), pp.229-263.
Cazzato, G., Daruish, M., Fortarezza, F., Colagrande, A., Marzullo, A., Ingravallo, G., Dei Tos, A.P., Yang, R.K., and Cho, W.C., 2025. Gene fusiondriven cutaneous adnexal neoplasms: An updated review emphasizing molecular characteristics. American Journal of Dermatopathology, 47(6), pp.453-461.
Chawsheen, M.A., Al-Naqshbandi, A.A., Ishaac, R.H., and Sur, F.A.K., 2025. Epidemiological trends and molecular characterization of breast carcinoma in Erbil, Kurdistan Region of Iraq. ARO - The Scientific Journal of Koya University, 13(1), pp.86-93.
Cocco, E., Scaltriti, M., and Drilon, A., 2018. NTRK fusion-positive cancers and TRK inhibitor therapy. Nature Reviews Clinical Oncology, 15(12), pp.731-747.
Demetri, G.D., De Braud, F., Drilon, A., Siena, S., Patel, M.R., Cho, B.C., Liu, S.V., Ahn, M.J., Chiu, C.H., Lin, J.J., Goto, K., Lee, J., Bazhenova, L., John, T.,… & Rolfo, C., 2022. Updated integrated analysis of the efficacy and safety of entrectinib in patients with NTRK fusion-positive solid tumors. Clinical Cancer Research, 28(7), pp.1302-1312.
Elhawary, N.A., Ekram, S.N., Sembawa, H.A., Tashkandi, E., Bannani, S., Azher, Z.A., Abumansour, I.S., Almuqati, R.M., Attieh, R., Sindi, I.A., Almutrafi, M., Alsobahi, F., Alghamdi, G., and Elhawary, A.N., 2025. Descriptive epidemiology of female breast cancer around the world: Incidence, mortality, and sociodemographic risks and disparities. International Journal of Environmental Health Research, 35, pp.3648-3662.
Gao, Q., Liang, W.W., Foltz, S.M., Mutharasu, G., Jayasinghe, R.G., Cao, S., Liao, W.W., Reynolds, S.M., Wyczalkowski, M.A., Yao, L., Yu, L., Sun, S.Q., Fusion Analysis Working Group.,… & Ding L., 2018. Driver fusions and their implications in the development and treatment of human cancers. Cell Reports, 23(1), pp.227-238.e3.
Ghilli, M., Mariniello, M.D., Scatena, C., Dosa, L., Traficante, G., Tamburini, A., Caporalini, C., Buccoliero, A.M., Facchini, F., Colizzi, L., Quattrini Li, A., Landucci, E., Manca, G., Naccarato, A.G.,… & Roncella, M., 2018. Male secretory breast cancer: Case in a 6-year-old boy with a peculiar gene duplication and review of the literature. Breast Cancer Research and Treatment, 170(3), pp.445-454.
Hade, I.M., and Hade, I.M., 2025. BRCA1 gene mutation of breast cancer in Iraq. GSC Biological and Pharmaceutical Sciences, 31(1), pp.280-283.
Hasan, F.F.H., Ali, F.A., Yahya, A.Q., and Hussain, A.F., 2024. Expression of the hopeful therapeutic target CD15 in women with breast cancer. AL-Kindy College Medical Journal, 20(3), pp.182-187.
Hong, D.S., DuBois, S.G., Kummar, S., Farago, A.F., Albert, C.M., Rohrberg, K.S., Van Tilburg, C.M., Nagasubramanian, R., Berlin, J.D., Federman, N., Mascarenhas, L., Geoerger, B., Dowlati, A., Pappo, A.S.,… & Drilon A., 2020. Larotrectinib in patients with TRK fusion-positive solid tumours: A pooled analysis of three phase 1/2 clinical trials. The Lancet Oncology, 21(4), pp.531-540.
Kerlikowske, K., Bissell, M.C.S., Sprague, B.L., Buist, D.S.M., Henderson, L.M., Lee, J.M., and Miglioretti, D.L., 2021. Advanced breast cancer definitions by staging system examined in the breast cancer surveillance consortium. Journal of the National Cancer Institute, 113(7), pp.909-916.
Kinnunen, M., Liu, X., Niemelä, E., Öhman, T., Gawriyski, L., Salokas, K., Keskitalo, S., and Varjosalo M., 2023. The impact of ETV6-NTRK3 oncogenic gene fusions on molecular and signaling pathway alterations. Cancers (Basel), 15(17), p.4246.
Marchiò, C., Scaltriti, M., Ladanyi, M., Iafrate, A.J., Bibeau, F., Dietel, M., Hechtman, J.F., Troiani, T., López-Rios, F., Douillard, J.Y., Andrè, F., and ReisFilho, J.S., 2019. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Annals of Oncology, 30(9), pp.1417-1427.
Md Nasir, N.D., Koh, V.C., Cree, I.A., Ruiz, B.I., Del Águila, J., Armon, S., Fox, S.B., Lakhani, S.R., and Tan, P.H., 2023. Phyllodes tumour evidence gaps mapped from the 5th edition of the WHO classification of tumours of the breast. Histopathology, 82(5), pp.704-712.
Medford, A.J., Oshry, L., Boyraz, B., Kiedrowski, L., Menshikova, S., Butusova, A., Dai, C.S., Gogakos, T., Keenan, J.C., Occhiogrosso, R.H., Ryan, P., Lennerz, J.K., Spring, L.M., Moy, B., Ellisen, L.W., and Bardia, A., 2023. TRK inhibitor in a patient with metastatic triple-negative breast cancer and NTRK fusions identified via cell-free DNA analysis. Therapeutic Advances in Medical Oncology, 15. pp.1-9.
Min, N., Zhu, J., Liu, M., and Li, X., 2022. Advancement of secretory breast carcinoma: A narrative review. Annals of Translational Medicine, 10(21), p.1178.
Mishra, P., Pandey, C.M., Singh, U., Gupta, A., Sahu, C., and Keshri, A., 2019. Descriptive statistics and normality tests for statistical data. Annals of Cardiac Anaesthesia, 22(1), pp.67-72.
Mohsin, R.N., and Mohamad, B.J., 2024. Clinical and histopathological features of breast cancer in Iraqi patients between 2018-2021. Iraqi Journal of Science, 65, pp.90-107.
O’Haire, S., Franchini, F., Kang, Y.J., Steinberg, J., Canfell, K., Desai, J., Fox, S., and IJzerman, M. 2023. Systematic review of NTRK 1/2/3 fusion prevalence pan-cancer and across solid tumours. Scientific Reports, 13(1), p.4116.
Rafiei, S., Pashazadeh Kan, F., Raoofi, S., Javan Biparva, A., and Ghashghaee, A., 2023. Middle Eastern patients with breast cancer and depression: A systematic review and meta-analysis. IJ Psychiatry and Behavioral Sciences, 17(3), p.e135463.
Rakaee, M., Andersen, S., Giannikou, K., Paulsen, E.E., Kilvær, T.K., Busund, L.T., Berg, T., Richardsen, E., Lombardi, A.P., Adib, E., Pedersen, M.I., Tafavvoghi, M., Wahl, S.G.F., Petersen, R.H., and Donnem, T., 2023. Machine learning-based immune phenotypes correlate with STK11/KEAP1 co-mutations and prognosis in resectable NSCLC: A sub-study of the TNM-I trial. Annals of Oncology, 34(7), pp.578-588.
Rudzinski, E.R., Lockwood, C.M., Stohr, B.A., Vargas, S.O., Sheridan, R., Black, J.O., Rajaram V, Laetsch, T.W., and Davis JL., 2018. Pan-Trk immunohistochemistry identifies NTRK rearrangements in pediatric mesenchymal tumors. American Journal of Surgical Pathology, 42(7), pp.927-935.
Sesé, M., Clavé, S., Somoza, R., Zafon, C., Iglesias, C., Hernando, J., Capdevila, J., Lloveras, B., Arumí, M., Torres, E., Vela, M.C., Bellosillo, B., and Hernandez-Losa, J., 2025. Implementation of NGS Analysis for the Detection of RET Rearrangements in Thyroid Cancer Patients. An Inter-Laboratory Validation of the Method. [Preprints].
Stockley, T.L., Lo, B., Box, A., Corredor, A.G., DeCoteau, J., Desmeules, P., Feilotter, H., Grafodatskaya, D., Greer, W., Hawkins, C., Huang, W.Y., Izevbaye, I., Lépine, G., Martins Filho, S.N.,… & Tsao, M.S., 2023. CANTRK: A Canadian ring study to optimize detection of NTRK gene fusions by next-generation RNA sequencing. Journal of Molecular Diagnostics, 25(3), pp.168-174.
Sullivan, L.M., 2023. Essentials of Biostatistics in Public Health. Jones and Bartlett Learning, United States.
Westphalen, C.B., Krebs, M.G., Le Tourneau, C., Sokol, E.S., Maund, S.L., Wilson, T.R., Jin, D.X., Newberg, J.Y., Fabrizio, D., Veronese, L., Thomas, M., and De Braud, F., 2021. Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population. NPJ Precision Oncology, 5(1), p.69.
Wu, S., Shi, X., Ren, X., Li, K., Pang, J., and Liang, Z., 2021. Evaluation of NTRK gene fusion by five different platforms in triple-negative breast carcinoma. Frontiers in Molecular Biosciences, 8, p.654387.
Yılmaz, F., Yaşar, S., Mandel, N.M., Kaçan, T., Özdemir, M., Doğu, G.G., Şengül, N., Meydan, N., Başal, F.B., Tolunay, P.K., Hamamcı, M.B., Dinçer, O.S., Bahçeci, A.,… & Yalçın Ş., 2024. Real-life experience with entrectinib in neurotrophic tyrosine receptor kinase fusion-positive solid tumors: A multicenter retrospective trial. Targeted Oncology, 19(6), pp.957-964.
Zhao, Y.Y., Ge, H.J., Yang, W.T., Shao, Z.M., and Hao, S., 2024. Secretory breast carcinoma: Clinicopathological features and prognosis of 52 patients. Breast Cancer Research and Treatment, 203(3), pp.543-551.
Zito Marino, F., Buono, S., Montella, M., Giannatiempo, R., Messina, F., Casaretta, G., Arpino, G., Vita, G., Fiorentino, F., Insabato, L., Sgambato, A., Orditura, M., Franco, R., and Accardo, M., 2023. NTRK gene aberrations in triple-negative breast cancer: Detection challenges using IHC, FISH, RT-PCR, and NGS. Journal of Pathology: Clinical Research, 9(5), pp.367-377.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Ammar K. Alzubaidi
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Authors who choose to publish their work with Aro agree to the following terms:
-
Authors retain the copyright to their work and grant the journal the right of first publication. The work is simultaneously licensed under a Creative Commons Attribution License [CC BY-NC-SA 4.0]. This license allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
-
Authors have the freedom to enter into separate agreements for the non-exclusive distribution of the journal's published version of the work. This includes options such as posting it to an institutional repository or publishing it in a book, as long as proper acknowledgement is given to its initial publication in this journal.
-
Authors are encouraged to share and post their work online, including in institutional repositories or on their personal websites, both prior to and during the submission process. This practice can lead to productive exchanges and increase the visibility and citation of the published work.
By agreeing to these terms, authors acknowledge the importance of open access and the benefits it brings to the scholarly community.
Accepted 2026-08-07
Published 2026-10-08
ARO Journal is a scientific, peer-reviewed, periodical, and diamond OAJ that has no APC or ASC.