oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2020-19-4-152-159oncotomsk-1544Research ArticleСЛУЧАЙ ИЗ КЛИНИЧЕСКОЙ ПРАКТИКИCASE REPORTSСПЕКТР СОМАТИЧЕСКИХ МУТАЦИЙ ПРИ ЗАБРЮШИННОЙ НЕОРГАННОЙ ЛЕЙОМИОСАРКОМЕ: КЛИНИЧЕСКИЙ СЛУЧАЙ И ОБЗОР ЛИТЕРАТУРЫSPECTRUM OF SOMATIC MUTATIONS IN RETROPERITONEAL LEIOMYOSARCOMA: CLINICAL CASE AND LITERATURE REVIEWhttps://orcid.org/0000-0002-2410-7801БугаёвВ. Е.BugaevV. E.

Бугаёв Владислав Евгеньевич, аспирант хирургического отделения № 6 абдоминальной онкологии торакоабдоминального отдела SPIN-код: 7913-4919. 

115478, г. Москва, Каширское шоссе, 24

Vladislav E. Bugaev, MD, Postgraduate, Surgery Department № 6 

23, Kashirskoye Shosse, 115478-Moscow

vladbugaev@mail.ruhttps://orcid.org/0000-0002-9608-4696НикулинМ. П.NikulinM. P.

Никулин Максим Петрович, кандидат медицинских наук, старший научный сотрудник хирургического отделения № 6 абдоминальной онкологии торакоабдоминального отдела НИИ клинической онкологии им. Н.Н. Трапезникова SPIN-код: 9455-5566.

115478, г. Москва, Каширское шоссе, 24

Maxim P. Nikulin, MD, PhD, Senior Researcher, Surgery Department 

23, Kashirskoye Shosse, 115478-Moscow

ГоловинаД. А.GolovinaD. A.

Головина Дарья Андреевна, кандидат биологических наук, научный сотрудник лаборатории клинической онкогенетики отдела морфологической и молекулярно-генетической диагностики опухолей

115478, г. Москва, Каширское шоссе, 24

Daria A. Golovina, PhD, Research Fellow, Oncogenetics Laboratory 

23, Kashirskoye Shosse, 115478-Moscow

СафроноваВ. М.SafronovaV. M.

Сафронова Вера Михайловна, младший научный сотрудник лаборатории клинической онкогенетики отдела морфологической и молекулярно-генетической диагностики опухолей

115478, г. Москва, Каширское шоссе, 24

Vera M. Safronova, Junior Research Fellow, Oncogenetics Laboratory 

23, Kashirskoye Shosse, 115478-Moscow

НередС. Н.NeredS. N.

Неред Сергей Николаевич, доктор медицинских наук, ведущий научный сотрудник хирургического отделения № 6 (абдоминальной онкологии) торако-абдоминального отдела, НИИ клинической онкологии им. Н.Н. Трапезникова SPIN-код: 4588-3230. AuthorID (РИНЦ): 394472.

115478, г. Москва, Каширское шоссе, 24

Sergei N. Nered, MD, DSc, Leading Researcher, Thoracic and Abdominal Department 

23, Kashirskoye Shosse, 115478-Moscow

ЛюбченкоЛ. Н.LyubchenkoL. N.

Любченко Людмила Николаевна, доктор медицинских наук, доцент кафедры онкологии института клинической медицины; заведующая лабораторией клинической онкогенетики отдела морфологической и молекулярно-генетической диагностики опухолей, НИИ клинической онкологии им. Н.Н. Трапезникова SPIN-код: 9589- 9057.

115478, г. Москва, Каширское шоссе, 24;119991, г. Москва, ул. Трубецкая, 8/2

Ludmila N. Lyubchenko, MD, DSC, Associate Professor, Oncology Institute of Clinical Medicine; Head of Laboratory of Clinical Oncogenetics, Department of Morphological and Molecular Genetic Diagnosis of Tumors 

23, Kashirskoye Shosse, 115478-Moscow;8-2, Trubetskaya str., Moscow-119991

https://orcid.org/0000-0002-5229-8203СтилидиИ. С.StilidiI. S.

Стилиди Иван Сократович, доктор медицинских наук, академик РАН, профессор, директор; заведующий отделением абдоминальной онкологии, НИИ клинической онкологии им. Н.Н. Трапезникова  SPIN-код: 9622-7106.

115478, г. Москва, Каширское шоссе, 24

Ivan S. Stilidi, MD, DSc, Professor, Member of the Russian Academy of Sciences, Director; Head of Surgical Department № 6 

23, Kashirskoye Shosse, 115478-Moscow

ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава РоссииРоссияN.N. Blokhin National Medical Research Centre of Oncology of the Health Ministry of RussiaRussian FederationФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России; ФГАОУ ВО «Первый МГМУ им. И.М. Сеченова Минздрава России (Сеченовский Университет)»РоссияN.N. Blokhin National Medical Research Centre of Oncology of the Health Ministry of Russia; I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University)Russian Federation202002092020194152159Copyright © Бугаёв В.Е., Никулин М.П., Головина Д.А., Сафронова В.М., Неред С.Н., Любченко Л.Н., Стилиди И.С., 20202020Бугаёв В.Е., Никулин М.П., Головина Д.А., Сафронова В.М., Неред С.Н., Любченко Л.Н., Стилиди И.С.Bugaev V.E., Nikulin M.P., Golovina D.A., Safronova V.M., Nered S.N., Lyubchenko L.N., Stilidi I.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/1544

Забрюшинные неорганные лейомиосаркомы являются высокоагрессивными опухолями и характеризуются неблагоприятным прогнозом, обусловленным низкой чувствительностью к химиотерапии. В настоящее время проводится поиск новых мишеней для лекарственного воздействия. В данной статье мы приводим клинический случай забрюшинной неорганной лейомиосаркомы с агрессивным течением, при которой был выявлен ряд ранее не описанных в литературе активирующих мутаций в генах, играющих важную роль в регуляции клеточной пролиферации. Больной в возрасте 61 года обратился в нашу клинику с жалобами на эпизодические боли в животе, повышение температуры тела. При обследовании был выявлен забрюшинно расположенный многоузловой опухолевый конгломерат, размерами 12×10 см. Пациенту было выполнено радикальное (R0) оперативное вмешательство в объёме удаления забрюшинной опухоли, левосторонней гемиколэктомии, нефрэктомии и адреналэктомии слева, дистальной субтотальной резекции поджелудочной железы. По данным патоморфологического исследования операционного материала опухоль соответствовала лейомиосаркоме III степени злокачественности (по системе FNCLCC). В послеоперационном периоде адъювантная химиотерапия не проводилась. В ранние сроки после операции (безрецидивный период – 3 мес) отмечено прогрессирование заболевания в виде локального рецидива опухоли и появления метастазов в лёгких, проводилась симптоматическая терапия. Спустя 6 мес после операции пациент скончался от прогрессирования заболевания. При иммуногистохимическом исследовании было выявлено, что в опухоли определяется экспрессия PD L1, уровень которой составил 30 %. Молекулярно-генетическое профилирование позволило выявить ряд соматических мутаций в генах PIK3CA, EGFR, ERBB2, PD GFRA, а также подтвердить стабильную систему репарации (MSS). Изучение мутационного профиля лейомиосарком представляет большой интерес, поскольку это может позволить определить новые механизмы лекарственного воздействия и улучшить результаты лечения.

Retroperitoneal leiomyosarcomas (RpLMS) are highly aggressive tumors, which are characterized by poor prognosis and resistance to chemotherapy. Targeting tumor-specific molecular pathways have become a rapidly expanding field in drug development to increase efficacy of treatment of LMS. Here we present a case report of rapidly progressive RpLMS with gene mutations of key molecular pathways, which have not previously described in the literature. A 61-year-old man was admitted to our hospital with complaints of abdominal pain and fever. Radiological examination revealed retroperitoneal leiomyosarcoma, which was histologically confirmed by core-biopsy. The patient underwent radical (R0) en-bloc resection of tumor with left hemicolectomy, left total nephrectomy, left total adrenalectomy and distal subtotal pancreatectomy. Pathological assessment of the tumor revealed G3 leiomyosarcoma. The patient did not receive adjuvant therapy. Disease progression (local recurrence and pulmonary metastases) occurred 3 months after surgery, and the patient died 6 months after surgery. Immunohistochemical study revealed positive PD -L1 expression in tumor cells. The percentage of PD -L1- expressing cells was 30 %. Molecular-genetic testing allowed identification of somatic mutations in genes, such as PIK3CA, ALK, EGFR, ERBB, ESR1 and PD GFRA and confirmation of microsatellite stable status (MSS) of the tumor. Further studies to investigate spectrum of mutations in RpLMS are of great interest, since they can allow identification of potential targets for more effective antitumor therapy and to improve treatment results.

лейомиосаркомамутационный профильтаргетная терапияleiomyosarcomamutationstargeted therapyReferencesYang J., Du X., Chen K., Ylipää A., Lazar A.J., Trent J., Lev D., Pollock R., Hao X., Hunt K., Zhang W. Genetic aberrations in soft tissue leiomyosarcoma. Cancer Lett. 2009 Mar 8; 275(1): 1–8. doi: 10.1016/j.canlet.2008.06.013.Yang J., Du X., Chen K., Ylipää A., Lazar A.J., Trent J., Lev D., Pollock R., Hao X., Hunt K., Zhang W. Genetic aberrations in soft tissue leiomyosarcoma. Cancer Lett. 2009 Mar 8; 275(1): 1–8. doi: 10.1016/j.canlet.2008.06.013.Larramendy M.L., Kaur S., Svarvar C., Böhling T., Knuutila S. Gene copy number profiling of soft-tissue leiomyosarcomas by arraycomparative genomic hybridization. Cancer Genet Cytogenet. 2006 Sep; 169(2): 94–101. doi: 10.1016/j.cancergencyto.2006.01.008.Larramendy M.L., Kaur S., Svarvar C., Böhling T., Knuutila S. Gene copy number profiling of soft-tissue leiomyosarcomas by arraycomparative genomic hybridization. Cancer Genet Cytogenet. 2006 Sep; 169(2): 94–101. doi: 10.1016/j.cancergencyto.2006.01.008.Guillou L., Aurias A. Soft tissue sarcomas with complex genomic profiles. Virchows Arch. 2010 Feb; 456(2): 201–17. doi: 10.1007/s00428-009-0853-4.Guillou L., Aurias A. Soft tissue sarcomas with complex genomic profiles. Virchows Arch. 2010 Feb; 456(2): 201–17. doi: 10.1007/s00428-009-0853-4.Gronchi A., Strauss D.C., Miceli R., Bonvalot S., Swallow C.J., Hohenberger P., Van Coevorden F., Rutkowski P., Callegaro D., Hayes A.J., Honoré C., Fairweather M., Cannell A., Jakob J., Haas R.L., Szacht M., Fiore M., Casali P.G., Pollock R.E., Raut C.P. Variability in Patterns of Recurrence After Resection of Primary Retroperitoneal Sarcoma (RPS): A Report on 1007 Patients From the Multi-institutional Collaborative RPS Working Group. Ann Surg. 2016 May; 263(5): 1002–9. doi: 10.1097/SLA.0000000000001447.Gronchi A., Strauss D.C., Miceli R., Bonvalot S., Swallow C.J., Hohenberger P., Van Coevorden F., Rutkowski P., Callegaro D., Hayes A.J., Honoré C., Fairweather M., Cannell A., Jakob J., Haas R.L., Szacht M., Fiore M., Casali P.G., Pollock R.E., Raut C.P. Variability in Patterns of Recurrence After Resection of Primary Retroperitoneal Sarcoma (RPS): A Report on 1007 Patients From the Multi-institutional Collaborative RPS Working Group. Ann Surg. 2016 May; 263(5): 1002–9. doi: 10.1097/SLA.0000000000001447.Toulmonde M., Bonvalot S., Méeus P., Stoeckle E., Riou O., Isambert N., Bompas E., Jafari M., Delcambre-Lair C., Saada E., Le Cesne A., Le Péchoux C., Blay J.Y., Piperno-Neumann S., Chevreau C., Bay J.O., Brouste V., Terrier P., Ranchère-Vince D., Neuville A., Italiano A.; French Sarcoma Group. Retroperitoneal sarcomas: patterns of care at diagnosis, prognostic factors and focus on main histological subtypes: a multicenter analysis of the French Sarcoma Group. Ann Oncol. 2014; 25(3): 735–742. doi: 10.1093/annonc/mdt577.Toulmonde M., Bonvalot S., Méeus P., Stoeckle E., Riou O., Isambert N., Bompas E., Jafari M., Delcambre-Lair C., Saada E., Le Cesne A., Le Péchoux C., Blay J.Y., Piperno-Neumann S., Chevreau C., Bay J.O., Brouste V., Terrier P., Ranchère-Vince D., Neuville A., Italiano A.; French Sarcoma Group. Retroperitoneal sarcomas: patterns of care at diagnosis, prognostic factors and focus on main histological subtypes: a multicenter analysis of the French Sarcoma Group. Ann Oncol. 2014; 25(3): 735–742. doi: 10.1093/annonc/mdt577.Hernando E., Charytonowicz E., Dudas M.E., Menendez S., Matushansky I., Mills J., Socci N.D., Behrendt N., Ma L., Maki R.G., Pandolfi P.P., Cordon-Cardo C. The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med. 2007 Jun; 13(6): 748–53. doi: 10.1038/nm1560.Hernando E., Charytonowicz E., Dudas M.E., Menendez S., Matushansky I., Mills J., Socci N.D., Behrendt N., Ma L., Maki R.G., Pandolfi P.P., Cordon-Cardo C. The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med. 2007 Jun; 13(6): 748–53. doi: 10.1038/nm1560.Ren W., Korchin B., Zhu Q.S., Wei C., Dicker A., Heymach J., Lazar A., Pollock R.E., Lev D. Epidermal growth factor receptor blockade in combination with conventional chemotherapy inhibits soft tissue sarcoma cell growth in vitro and in vivo. Clin Cancer Res. 2008 May 1; 14(9): 2785–95. doi: 10.1158/1078-0432.CCR-07-4471.Ren W., Korchin B., Zhu Q.S., Wei C., Dicker A., Heymach J., Lazar A., Pollock R.E., Lev D. Epidermal growth factor receptor blockade in combination with conventional chemotherapy inhibits soft tissue sarcoma cell growth in vitro and in vivo. Clin Cancer Res. 2008 May 1; 14(9): 2785–95. doi: 10.1158/1078-0432.CCR-07-4471.Fourneaux B., Chaire V., Lucchesi C., Karanian M., Pineau R., Laroche-Clary A., Italiano A. Dual inhibition of the PI3K/AKT/mTOR pathway suppresses the growth of leiomyosarcomas but leads to ERK activation through mTORC2: biological and clinical implications. Oncotarget. 2017; 8(5): 7878–90. doi: 10.18632/oncotarget.13987.Fourneaux B., Chaire V., Lucchesi C., Karanian M., Pineau R., Laroche-Clary A., Italiano A. Dual inhibition of the PI3K/AKT/mTOR pathway suppresses the growth of leiomyosarcomas but leads to ERK activation through mTORC2: biological and clinical implications. Oncotarget. 2017; 8(5): 7878–90. doi: 10.18632/oncotarget.13987.Mohseni M., Park B.H. PIK3CA and KRAS mutations predict for response to everolimus therapy: now that's RAD001. J Clin Invest. 2010 Aug; 120(8): 2655–8. doi: 10.1172/JCI44026.Mohseni M., Park B.H. PIK3CA and KRAS mutations predict for response to everolimus therapy: now that's RAD001. J Clin Invest. 2010 Aug; 120(8): 2655–8. doi: 10.1172/JCI44026.Alvarez K., Orellana P., Villarroel C., Contreras L., Kawachi H., Kobayashi M., Wielandt A.M., De la Fuente M., Triviño J.C., Kronberg U., Carvallo P., López-Köstner F. EGFR pathway subgroups in Chilean colorectal cancer patients, detected by mutational and expression profiles, associated to different clinicopathological features. Tumour Biol. 2017 Sep; 39(9): 1010428317724517. doi: 10.1177/1010428317724517.Alvarez K., Orellana P., Villarroel C., Contreras L., Kawachi H., Kobayashi M., Wielandt A.M., De la Fuente M., Triviño J.C., Kronberg U., Carvallo P., López-Köstner F. EGFR pathway subgroups in Chilean colorectal cancer patients, detected by mutational and expression profiles, associated to different clinicopathological features. Tumour Biol. 2017 Sep; 39(9): 1010428317724517. doi: 10.1177/1010428317724517.Peterson L.M., Kipp B.R., Halling K.C., Kerr S.E., Smith D.I., Distad T.J., Clayton A.C., Medeiros F. Molecular characterization of endometrial cancer: a correlative study assessing microsatellite instability, MLH1 hypermethylation, DNA mismatch repair protein expression, and PTEN, PIK3CA, KRAS, and BRAF mutation analysis. Int J Gynecol Pathol. 2012 May; 31(3): 195–205. doi: 10.1097/PGP.0b013e318231fc51.Peterson L.M., Kipp B.R., Halling K.C., Kerr S.E., Smith D.I., Distad T.J., Clayton A.C., Medeiros F. Molecular characterization of endometrial cancer: a correlative study assessing microsatellite instability, MLH1 hypermethylation, DNA mismatch repair protein expression, and PTEN, PIK3CA, KRAS, and BRAF mutation analysis. Int J Gynecol Pathol. 2012 May; 31(3): 195–205. doi: 10.1097/PGP.0b013e318231fc51.Hohensee I., Lamszus K., Riethdorf S., Meyer-Staeckling S., Glatzel M., Matschke J., Witzel I., Westphal M., Brandt B., Müller V., Pantel K., Wikman H. Frequent genetic alterations in EGFR- and HER2-driven pathways in breast cancer brain metastases. Am J Pathol. 2013 Jul; 183(1): 83–95. doi: 10.1016/j.ajpath.2013.03.023.Hohensee I., Lamszus K., Riethdorf S., Meyer-Staeckling S., Glatzel M., Matschke J., Witzel I., Westphal M., Brandt B., Müller V., Pantel K., Wikman H. Frequent genetic alterations in EGFR- and HER2-driven pathways in breast cancer brain metastases. Am J Pathol. 2013 Jul; 183(1): 83–95. doi: 10.1016/j.ajpath.2013.03.023.Abubaker J., Bavi P., Al-Harbi S., Ibrahim M., Siraj A.K., Al-Sanea N., Abduljabbar A., Ashari L.H., Alhomoud S., Al-Dayel F., Uddin S., Al-Kuraya K.S. Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population. Oncogene. 2008 Jun 5; 27(25): 3539–45. doi: 10.1038/sj.onc.1211013.Abubaker J., Bavi P., Al-Harbi S., Ibrahim M., Siraj A.K., Al-Sanea N., Abduljabbar A., Ashari L.H., Alhomoud S., Al-Dayel F., Uddin S., Al-Kuraya K.S. Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population. Oncogene. 2008 Jun 5; 27(25): 3539–45. doi: 10.1038/sj.onc.1211013.Lassman A.B., Rossi M.R., Raizer J.J., Abrey L.E., Lieberman F.S., Grefe C.N., Lamborn K., Pao W., Shih A.H., Kuhn J.G., Wilson R., Nowak N.J., Cowell J.K., DeAngelis L.M., Wen P., Gilbert M.R., Chang S., Yung W.A., Prados M., Holland E.C. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01. Clin Cancer Res. 2005 Nov 1; 11(21): 7841–50. doi: 10.1158/1078-0432.CCR-05-0421.Lassman A.B., Rossi M.R., Raizer J.J., Abrey L.E., Lieberman F.S., Grefe C.N., Lamborn K., Pao W., Shih A.H., Kuhn J.G., Wilson R., Nowak N.J., Cowell J.K., DeAngelis L.M., Wen P., Gilbert M.R., Chang S., Yung W.A., Prados M., Holland E.C. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01. Clin Cancer Res. 2005 Nov 1; 11(21): 7841–50. doi: 10.1158/1078-0432.CCR-05-0421.rs2227983 (SNP) ‑ Explore this variant ‑ Homo sapiens ‑ Ensembl genome browser 96 [Internet]. URL: https://www.ensembl.org/Homo_sapiens/Variation/Explore?r=7:55161062-55162062;v=rs2227983;vdb=variation;vf=415993233 (cited 23.04.2019).rs2227983 (SNP) ‑ Explore this variant ‑ Homo sapiens ‑ Ensembl genome browser 96 [Internet]. URL: https://www.ensembl.org/Homo_sapiens/Variation/Explore?r=7:55161062-55162062;v=rs2227983;vdb=variation;vf=415993233 (cited 23.04.2019).Wang W.S., Chen P.M., Chiou T.J., Liu J.H., Lin J.K., Lin T.C., Wang H.S., Su Y. Epidermal growth factor receptor R497K polymorphism is a favorable prognostic factor for patients with colorectal carcinoma. Clin Cancer Res. 2007 Jun 15; 13(12): 3597–604. doi: 10.1158/1078-0432.CCR-06-2601.Wang W.S., Chen P.M., Chiou T.J., Liu J.H., Lin J.K., Lin T.C., Wang H.S., Su Y. Epidermal growth factor receptor R497K polymorphism is a favorable prognostic factor for patients with colorectal carcinoma. Clin Cancer Res. 2007 Jun 15; 13(12): 3597–604. doi: 10.1158/1078-0432.CCR-06-2601.Zhang W., Park D.J., Lu B., Yang D.Y., Gordon M., Groshen S., Yun J., Press O.A., Vallböhmer D., Rhodes K., Lenz H.J. Epidermal growth factor receptor gene polymorphisms predict pelvic recurrence in patients with rectal cancer treated with chemoradiation. Clin Cancer Res. 2005 Jan 15; 11(2 Pt 1): 600–5.Zhang W., Park D.J., Lu B., Yang D.Y., Gordon M., Groshen S., Yun J., Press O.A., Vallböhmer D., Rhodes K., Lenz H.J. Epidermal growth factor receptor gene polymorphisms predict pelvic recurrence in patients with rectal cancer treated with chemoradiation. Clin Cancer Res. 2005 Jan 15; 11(2 Pt 1): 600–5.Hsieh Y.Y., Tzeng C.H., Chen M.H., Chen P.M., Wang W.S. Epidermal growth factor receptor R521K polymorphism shows favorable outcomes in KRAS wild-type colorectal cancer patients treated with cetuximab-based chemotherapy. Cancer Sci. 2012 Apr; 103(4): 791–6. doi: 10.1111/j.1349-7006.2012.02225.x.Hsieh Y.Y., Tzeng C.H., Chen M.H., Chen P.M., Wang W.S. Epidermal growth factor receptor R521K polymorphism shows favorable outcomes in KRAS wild-type colorectal cancer patients treated with cetuximab-based chemotherapy. Cancer Sci. 2012 Apr; 103(4): 791–6. doi: 10.1111/j.1349-7006.2012.02225.x.Kallel I., Rebai M., Khabir A., Farid N.R., Rebaï A. Genetic polymorphisms in the EGFR (R521K) and estrogen receptor (T594T) genes, EGFR and ErbB-2 protein expression, and breast cancer risk in Tunisia. J Biomed Biotechnol. 2009; 2009: 753683. doi: 10.1155/2009/753683.Kallel I., Rebai M., Khabir A., Farid N.R., Rebaï A. Genetic polymorphisms in the EGFR (R521K) and estrogen receptor (T594T) genes, EGFR and ErbB-2 protein expression, and breast cancer risk in Tunisia. J Biomed Biotechnol. 2009; 2009: 753683. doi: 10.1155/2009/753683.rs2293347 (SNP) ‑ Explore this variant ‑ Homo sapiens ‑ Ensembl genome browser 96 [Internet]. URL: https://www.ensembl.org/Homo_sapiens/Variation/Explore?r=7:55200723-55201723;v=rs2293347;vdb=variation;vf=415996799 (cited 23.04.2019).rs2293347 (SNP) ‑ Explore this variant ‑ Homo sapiens ‑ Ensembl genome browser 96 [Internet]. URL: https://www.ensembl.org/Homo_sapiens/Variation/Explore?r=7:55200723-55201723;v=rs2293347;vdb=variation;vf=415996799 (cited 23.04.2019).Zhang L., Yuan X., Chen Y., Du X.J., Yu S., Yang M. Role of EGFR SNPs in survival of advanced lung adenocarcinoma patients treated with Gefitinib. Gene. 2013 Mar 15; 517(1): 60–4. doi: 10.1016/j.gene.2012.12.087.Zhang L., Yuan X., Chen Y., Du X.J., Yu S., Yang M. Role of EGFR SNPs in survival of advanced lung adenocarcinoma patients treated with Gefitinib. Gene. 2013 Mar 15; 517(1): 60–4. doi: 10.1016/j.gene.2012.12.087.Wang W., Ma X.P., Shi Z., Zhang P., Ding D.L., Huang H.X., Saiyin H.G., Chen T.Y., Lu P.X., Wang N.J., Yu H., Sun J., Zheng S.L., Yu L., Xu J., Jiang D.K. Epidermal growth factor receptor pathway polymorphisms and the prognosis of hepatocellular carcinoma. Am J Cancer Res. 2014 Dec 15; 5(1): 396–410.Wang W., Ma X.P., Shi Z., Zhang P., Ding D.L., Huang H.X., Saiyin H.G., Chen T.Y., Lu P.X., Wang N.J., Yu H., Sun J., Zheng S.L., Yu L., Xu J., Jiang D.K. Epidermal growth factor receptor pathway polymorphisms and the prognosis of hepatocellular carcinoma. Am J Cancer Res. 2014 Dec 15; 5(1): 396–410.Toomey S., Madden S.F., Furney S.J., Fan Y., McCormack M., Stapleton C., Cremona M., Cavalleri G.L., Milewska M., Elster N., Carr A., Fay J., Kay E.W., Kennedy S., Crown J., Gallagher W.M., Hennessy B.T., Eustace A.J. The impact of ERBB-family germline single nucleotide polymorphisms on survival response to adjuvant trastuzumab treatment in HER2-positive breast cancer. Oncotarget. 2016 Nov; 7(46): 75518–525. doi: 10.18632/oncotarget.12782.Toomey S., Madden S.F., Furney S.J., Fan Y., McCormack M., Stapleton C., Cremona M., Cavalleri G.L., Milewska M., Elster N., Carr A., Fay J., Kay E.W., Kennedy S., Crown J., Gallagher W.M., Hennessy B.T., Eustace A.J. The impact of ERBB-family germline single nucleotide polymorphisms on survival response to adjuvant trastuzumab treatment in HER2-positive breast cancer. Oncotarget. 2016 Nov; 7(46): 75518–525. doi: 10.18632/oncotarget.12782.Lee P.J., Yoo N.S., Hagemann I.S., Pfeifer J.D., Cottrell C.E., Abel H.J., Duncavage E.J. Spectrum of mutations in leiomyosarcomas identified by clinical targeted next-generation sequencing. Exp Mol Pathol. 2017 Feb; 102(1): 156–161. doi: 10.1016/j.yexmp.2017.01.012.Lee P.J., Yoo N.S., Hagemann I.S., Pfeifer J.D., Cottrell C.E., Abel H.J., Duncavage E.J. Spectrum of mutations in leiomyosarcomas identified by clinical targeted next-generation sequencing. Exp Mol Pathol. 2017 Feb; 102(1): 156–161. doi: 10.1016/j.yexmp.2017.01.012.Bocharov E.V., Mineev K.S., Volynsky P.E., Ermolyuk Y.S., Tkach E.N., Sobol A.G., Chupin V.V., Kirpichnikov M.P., Efremov R.G., Arseniev A.S. Spatial structure of the dimeric transmembrane domain of the growth factor receptor ErbB2 presumably corresponding to the receptor active state. J Biol Chem. 2008 Mar 14; 283(11): 6950–6. doi: 10.1074/jbc.M709202200.Bocharov E.V., Mineev K.S., Volynsky P.E., Ermolyuk Y.S., Tkach E.N., Sobol A.G., Chupin V.V., Kirpichnikov M.P., Efremov R.G., Arseniev A.S. Spatial structure of the dimeric transmembrane domain of the growth factor receptor ErbB2 presumably corresponding to the receptor active state. J Biol Chem. 2008 Mar 14; 283(11): 6950–6. doi: 10.1074/jbc.M709202200.Moasser M.M. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007 Oct 4; 26(45): 6469–87. doi: 10.1038/sj.onc.1210477.Moasser M.M. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007 Oct 4; 26(45): 6469–87. doi: 10.1038/sj.onc.1210477.Fleishman S.J., Schlessinger J., Ben-Tal N. A putative molecular-activation switch in the transmembrane domain of erbB2. Proc Natl Acad Sci U S A. 2002 Dec 10; 99(25): 15937–40. doi: 10.1073/pnas.252640799.Fleishman S.J., Schlessinger J., Ben-Tal N. A putative molecular-activation switch in the transmembrane domain of erbB2. Proc Natl Acad Sci U S A. 2002 Dec 10; 99(25): 15937–40. doi: 10.1073/pnas.252640799.Stanton S.E., Ward M.M., Christos P., Sanford R., Lam C., Cobham M.V., Donovan D., Scheff R.J., Cigler T., Moore A., Vahdat L.T., Lane M.E., Chuang E. Pro1170 Ala polymorphism in HER2-neu is associated with risk of trastuzumab cardiotoxicity. BMC Cancer. 2015; 15: 267. doi: 10.1186/s12885-015-1298-6.Stanton S.E., Ward M.M., Christos P., Sanford R., Lam C., Cobham M.V., Donovan D., Scheff R.J., Cigler T., Moore A., Vahdat L.T., Lane M.E., Chuang E. Pro1170 Ala polymorphism in HER2-neu is associated with risk of trastuzumab cardiotoxicity. BMC Cancer. 2015; 15: 267. doi: 10.1186/s12885-015-1298-6.Benusiglio P.R., Lesueur F., Luccarini C., Conroy D.M., Shah M., Easton D.F., Day N.E., Dunning A.M., Pharoah P.D., Ponder B.A. Common ERBB2 polymorphisms and risk of breast cancer in a white British population: a case-control study. Breast Cancer Res. 2005; 7(2): R204–9. doi: 10.1186/bcr982.Benusiglio P.R., Lesueur F., Luccarini C., Conroy D.M., Shah M., Easton D.F., Day N.E., Dunning A.M., Pharoah P.D., Ponder B.A. Common ERBB2 polymorphisms and risk of breast cancer in a white British population: a case-control study. Breast Cancer Res. 2005; 7(2): R204–9. doi: 10.1186/bcr982.Kong S.L., Liu X., Suhaimi N.M., Koh K.J.H., Hu M., Lee D.Y.S., Cima I., Phyo W.M., Lee E.X.W., Tai J.A., Foong Y.M., Vo J.H., Koh P.K., Zhang T., Ying J.Y., Lim B., Tan M.H., Hillmer A.M. Molecular characterization of circulating colorectal tumor cells defines genetic signatures for individualized cancer care. Oncotarget. 2017 Jul; 8(40): 68026–037. doi: 10.18632/oncotarget.19138.Kong S.L., Liu X., Suhaimi N.M., Koh K.J.H., Hu M., Lee D.Y.S., Cima I., Phyo W.M., Lee E.X.W., Tai J.A., Foong Y.M., Vo J.H., Koh P.K., Zhang T., Ying J.Y., Lim B., Tan M.H., Hillmer A.M. Molecular characterization of circulating colorectal tumor cells defines genetic signatures for individualized cancer care. Oncotarget. 2017 Jul; 8(40): 68026–037. doi: 10.18632/oncotarget.19138.Kohsaka S., Shukla N., Ameur N., Ito T., Ng C.K., Wang L., Lim D., Marchetti A., Viale A., Pirun M., Socci N.D., Qin L.X., Sciot R., Bridge J., Singer S., Meyers P., Wexler L.H., Barr F.G., Dogan S., Fletcher J.A., Reis-Filho J.S., Ladanyi M. A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nat Genet. 2014; 46(6): 595–600. doi: 10.1038/ng.2969.Kohsaka S., Shukla N., Ameur N., Ito T., Ng C.K., Wang L., Lim D., Marchetti A., Viale A., Pirun M., Socci N.D., Qin L.X., Sciot R., Bridge J., Singer S., Meyers P., Wexler L.H., Barr F.G., Dogan S., Fletcher J.A., Reis-Filho J.S., Ladanyi M. A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nat Genet. 2014; 46(6): 595–600. doi: 10.1038/ng.2969.Shankar G.M., Taylor-Weiner A., Lelic N., Jones R.T., Kim J.C., Francis J.M., Abedalthagafi M., Borges L.F., Coumans J.V., Curry W.T., Nahed B.V., Shin J.H., Paek S.H., Park S.H., Stewart C., Lawrence M.S., Cibulskis K., Thorner A.R., Van Hummelen P., Stemmer-Rachamimov A.O., Batchelor T.T., Carter S.L., Hoang M.P., Santagata S., Louis D.N., Barker F.G., Meyerson M., Getz G., Brastianos P.K., Cahill D.P. Sporadic hemangioblastomas are characterized by cryptic VHL inactivation. Acta Neuropathol Commun. 2014 Dec 24; 2: 167. doi: 10.1186/s40478-014-0167-x.Shankar G.M., Taylor-Weiner A., Lelic N., Jones R.T., Kim J.C., Francis J.M., Abedalthagafi M., Borges L.F., Coumans J.V., Curry W.T., Nahed B.V., Shin J.H., Paek S.H., Park S.H., Stewart C., Lawrence M.S., Cibulskis K., Thorner A.R., Van Hummelen P., Stemmer-Rachamimov A.O., Batchelor T.T., Carter S.L., Hoang M.P., Santagata S., Louis D.N., Barker F.G., Meyerson M., Getz G., Brastianos P.K., Cahill D.P. Sporadic hemangioblastomas are characterized by cryptic VHL inactivation. Acta Neuropathol Commun. 2014 Dec 24; 2: 167. doi: 10.1186/s40478-014-0167-x.Forbes S.A., Beare D., Boutselakis H., Bamford S., Bindal N., Tate J., Cole C.G., Ward S., Dawson E., Ponting L., Stefancsik R., Harsha B., Kok C.Y., Jia M., Jubb H., Sondka Z., Thompson S., De T., Campbell P.J. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res. 2017 Jan 4; 45(D1): D777‑D783. doi: 10.1093/nar/gkw1121.Forbes S.A., Beare D., Boutselakis H., Bamford S., Bindal N., Tate J., Cole C.G., Ward S., Dawson E., Ponting L., Stefancsik R., Harsha B., Kok C.Y., Jia M., Jubb H., Sondka Z., Thompson S., De T., Campbell P.J. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res. 2017 Jan 4; 45(D1): D777‑D783. doi: 10.1093/nar/gkw1121.Xin D.J., Shen G.D., Song J. Single nucleotide polymorphisms of HER2 related to osteosarcoma susceptibility. Int J Clin Exp Pathol. 2015 Aug; 8(8): 9494–9.Xin D.J., Shen G.D., Song J. Single nucleotide polymorphisms of HER2 related to osteosarcoma susceptibility. Int J Clin Exp Pathol. 2015 Aug; 8(8): 9494–9.Wang V., Chuang T.C., Kao M.C., Shan D.E., Soong B.W., Shieh T.M. Polymorphic Ala-allele carriers at residue 1170 of HER2 associated with Parkinson’s disease. J Neurol Sci. 2013 Feb; 325(1–2): 115–9. doi: 10.1016/j.jns.2012.12.017.Wang V., Chuang T.C., Kao M.C., Shan D.E., Soong B.W., Shieh T.M. Polymorphic Ala-allele carriers at residue 1170 of HER2 associated with Parkinson’s disease. J Neurol Sci. 2013 Feb; 325(1–2): 115–9. doi: 10.1016/j.jns.2012.12.017.Ng P.K., Li J., Jeong K.J., Shao S., Chen H., Tsang Y.H., Sengupta S., Wang Z., Bhavana V.H., Tran R., Soewito S., Minussi D.C., Moreno D., Kong K., Dogruluk T., Lu H., Gao J., Tokheim C., Zhou D.C., Johnson A.M., Zeng J., Ip C.K.M., Ju Z, Wester M, Yu S, Li Y, Vellano CP, Schultz N, Karchin R, Ding L, Lu Y, Cheung L.W.T., Chen K., Shaw K.R., Meric-Bernstam F., Scott K.L., Yi S., Sahni N., Liang H., Mills G.B. Systematic Functional Annotation of Somatic Mutations in Cancer. Cancer Cell. 2018 Mar 12; 33(3): 450‑462.e10. doi: 10.1016/j.ccell.2018.01.021.Ng P.K., Li J., Jeong K.J., Shao S., Chen H., Tsang Y.H., Sengupta S., Wang Z., Bhavana V.H., Tran R., Soewito S., Minussi D.C., Moreno D., Kong K., Dogruluk T., Lu H., Gao J., Tokheim C., Zhou D.C., Johnson A.M., Zeng J., Ip C.K.M., Ju Z, Wester M, Yu S, Li Y, Vellano CP, Schultz N, Karchin R, Ding L, Lu Y, Cheung L.W.T., Chen K., Shaw K.R., Meric-Bernstam F., Scott K.L., Yi S., Sahni N., Liang H., Mills G.B. Systematic Functional Annotation of Somatic Mutations in Cancer. Cancer Cell. 2018 Mar 12; 33(3): 450‑462.e10. doi: 10.1016/j.ccell.2018.01.021.Longatto-Filho A., Pinheiro C., Martinho O., Moreira M.A., Ribeiro L.F., Queiroz G.S., Schmitt F.C., Baltazar F., Reis R.M. Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma. BMC Cancer. 2009 Jun 29; 9: 212. doi: 10.1186/1471-2407-9-212.Longatto-Filho A., Pinheiro C., Martinho O., Moreira M.A., Ribeiro L.F., Queiroz G.S., Schmitt F.C., Baltazar F., Reis R.M. Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma. BMC Cancer. 2009 Jun 29; 9: 212. doi: 10.1186/1471-2407-9-212.Taja-Chayeb L., Chavez-Blanco A., Martínez-Tlahuel J., González-Fierro A., Candelaria M., Chanona-Vilchis J., Robles E., Dueñas-Gonzalez A. Expression of platelet derived growth factor family members and the potential role of imatinib mesylate for cervical cancer. Cancer Cell Int. 2006 Oct 2; 6: 22. doi: 10.1186/1475-2867-6-22.Taja-Chayeb L., Chavez-Blanco A., Martínez-Tlahuel J., González-Fierro A., Candelaria M., Chanona-Vilchis J., Robles E., Dueñas-Gonzalez A. Expression of platelet derived growth factor family members and the potential role of imatinib mesylate for cervical cancer. Cancer Cell Int. 2006 Oct 2; 6: 22. doi: 10.1186/1475-2867-6-22.Estevez-Garcia P., Castaño A., Martin A.C., Lopez-Rios F., Iglesias J., Muñoz-Galván S., Lopez-Calderero I., Molina-Pinelo S., Pastor M.D., Carnero A., Paz-Ares L., Garcia-Carbonero R. PDGFRα/β and VEGFR2 polymorphisms in colorectal cancer: incidence and implications in clinical outcome. BMC Cancer. 2012 Nov 12; 12: 514. doi: 10.1186/1471-2407-12-514.Estevez-Garcia P., Castaño A., Martin A.C., Lopez-Rios F., Iglesias J., Muñoz-Galván S., Lopez-Calderero I., Molina-Pinelo S., Pastor M.D., Carnero A., Paz-Ares L., Garcia-Carbonero R. PDGFRα/β and VEGFR2 polymorphisms in colorectal cancer: incidence and implications in clinical outcome. BMC Cancer. 2012 Nov 12; 12: 514. doi: 10.1186/1471-2407-12-514.Trojani A., Ripamonti C.B., Penco S., Beghini A., Nadali G., Di Bona E., Viola A., Castagnola C., Colapietro P., Grillo G., Pezzetti L., Ravelli E., Patrosso M.C., Marocchi A., Cuneo A., Ferrara F., Lazzarino M., Pizzolo G., Cairoli R., Morra E. Molecular analysis of PDGFRA and PDGFRB genes by rapid single-strand conformation polymorphism (SSCP) in patients with core-binding factor leukaemias with KIT or FLT3 mutation. Anticancer Res. 2008; 28(5A): 2745–51.Trojani A., Ripamonti C.B., Penco S., Beghini A., Nadali G., Di Bona E., Viola A., Castagnola C., Colapietro P., Grillo G., Pezzetti L., Ravelli E., Patrosso M.C., Marocchi A., Cuneo A., Ferrara F., Lazzarino M., Pizzolo G., Cairoli R., Morra E. Molecular analysis of PDGFRA and PDGFRB genes by rapid single-strand conformation polymorphism (SSCP) in patients with core-binding factor leukaemias with KIT or FLT3 mutation. Anticancer Res. 2008; 28(5A): 2745–51.Gilbert J.A., Adhikari L.J., Lloyd R.V., Halfdanarson T.R., Muders M.H., Ames M.M. Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors. Pancreas. 2013; 42(3): 411–21. doi: 10.1097/MPA.0b013e31826cb243.Gilbert J.A., Adhikari L.J., Lloyd R.V., Halfdanarson T.R., Muders M.H., Ames M.M. Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors. Pancreas. 2013; 42(3): 411–21. doi: 10.1097/MPA.0b013e31826cb243.Martinho O., Longatto-Filho A., Lambros M.B., Martins A., Pinheiro C., Silva A., Pardal F., Amorim J., Mackay A., Milanezi F., Tamber N., Fenwick K., Ashworth A., Reis-Filho J.S., Lopes J.M., Reis R.M. Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas. Br J Cancer. 2009 Sep 15; 101(6): 973–82. doi: 10.1038/sj.bjc.6605225.Martinho O., Longatto-Filho A., Lambros M.B., Martins A., Pinheiro C., Silva A., Pardal F., Amorim J., Mackay A., Milanezi F., Tamber N., Fenwick K., Ashworth A., Reis-Filho J.S., Lopes J.M., Reis R.M. Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas. Br J Cancer. 2009 Sep 15; 101(6): 973–82. doi: 10.1038/sj.bjc.6605225.rs1873778 (SNP) ‑ Explore this variant ‑ Homo sapiens ‑ Ensembl genome browser 96 [Internet]. URL: https://www.ensembl.org/Homo_sapiens/Variation/Explore?r=4:54274388-54275388;v=rs1873778;vdb=variation;vf=250182332 (cited: 23.04.2019).rs1873778 (SNP) ‑ Explore this variant ‑ Homo sapiens ‑ Ensembl genome browser 96 [Internet]. URL: https://www.ensembl.org/Homo_sapiens/Variation/Explore?r=4:54274388-54275388;v=rs1873778;vdb=variation;vf=250182332 (cited: 23.04.2019).

The authors declare that there are no conflicts of interest present.