Mutation situations of KRAS and BRAF genes in gastrointestinal stromal tumors and its clinical significances_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

DANG Yunzhi ,  LI Jian , GAO Jing , LI Yanyan , GONG Jifang , LI Jie , LI Yan , WANG Xicheng ,  SHEN Lin

Department of Gastrointestinal Oncology, Beijing Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100142, P.R.China;

Corresponding author：

SHEN Lin, Email: linshenpku@163.com

Keywords：

gastrointestinal stromal tumors; KRAS; BRAF; gene mutation

DOI：

10.7507/1007-9424.201701004

Video：

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Objective To detective KRAS and BRAF mutations in gastrointestinal stromal tumors (GISTs) and explore its significance in resistance of imatinib treatment. Methods Three hundred and eighty-one c-kit/PDGFRA mutation samples, 119 c-kit/PDGFRA wild type samples, and 19 pairs of samples before and after imatinib resistance from 519 patients with GIST were enrolled in this study. Polymerase chain reaction was used to detect KRAS exon 2 and BRAF exon 15 mutations. The survival data were evaluated in patients with KRAS or BRAF mutation. Results KRAS mutation was found in 2 cases (1.7%) of c-kit /PDGFRA wild type GISTs, the type of KRAS mutation was G12D and G12C, respectively. BRAF^V600E mutation was found in 2 cases (1.7%) of wild type GISTs. No KRAS and BRAF mutations were found in the patients with the c-kit/PDGFRA mutation GISTs and pairs of GISTs before and after imatinib resistance. Two patients with KRAS mutation showed shorter progression free survivals for imatinib treatment. Two patients with BRAF mutation had longer recurrence free survivals. Conclusions Low frequency of KRAS or BRAF mutation only happens in wild type GISTs. KRAS mutation might be related to imatinib primary resistance, but not to secondary resistance.

Citation： DANGYunzhi, LIJian, GAOJing, LIYanyan, GONGJifang, LIJie, LIYan, WANGXicheng, SHENLin. Mutation situations of KRAS and BRAF genes in gastrointestinal stromal tumors and its clinical significances. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2017, 24(2): 154-157. doi: 10.7507/1007-9424.201701004 Copy

1.	Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet, 2007, 369(9574): 1731-1741.
2.	Maleddu A, Pantaleo MA, Nannini M,et al. The role of mutational analysis of KIT and PDGFRA in gastrointestinal stromal tumors in a clinical setting. J Transl Med, 2011, 9: 75.
3.	Demetri GD, von Mehren M, Blanke CD,et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med, 2002, 347(7): 472-480.
4.	Miettinen M, Lasota J. Histopathology of gastrointestinal stromal tumor. J Surg Oncol, 2011, 104(8): 865-873.
5.	Dadzie OE, Yang S, Emley A,et al. RAS and RAF mutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis. Br J Dermatol, 2009, 160(2): 368-375.
6.	Agaram NP, Wong GC, Guo T,et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer, 2008, 47(10): 853-859.
7.	Agaimy A, Terracciano LM, Dirnhofer S,et al. V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours. J Clin Pathol, 2009, 62(7): 613-616.
8.	Miranda C, Nucifora M, Molinari F,et al. KRAS and BRAF mutations predict primary resistance to imatinib in gastrointestinal stromal tumors. Clin Cancer Res, 2012, 18(6): 1769-1776.
9.	Daniels M, Lurkin I, Pauli R,et al. Spectrum of KIT/ PDGFRA/BRAF mutations and phosphatidylinositol-3-kinase pathway gene alterations in gastrointestinal stromal tumors (GIST). Cancer Lett, 2011, 312(1): 43-54.
10.	Lasota J, Xi L, Coates T, Dennis R,et al. No KRAS mutations found in gastrointestinal stromal tumors (GISTs): molecular genetic study of 514 cases. Mod Pathol, 2013, 26(11): 1488-1491.
11.	Fernández-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer, 2011, 2(3): 344-358.
12.	Davies H, Bignell GR, Cox C,et al. Mutations of the BRAF gene in human cancer. Nature, 2002, 417(6892): 949-954.
13.	Benesova L, Minarik M, Jancarikova D,et al. Multiplicity of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors. Anticancer Res, 2010, 30(5): 1667-1671.
14.	Dadzie OE, Yang S, Emley A,et al. RAS and RAF mutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis. Br J Dermatol, 2009, 160(2): 368-375.
15.	Loupakis F, Pollina L, Stasi I,et al. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol, 2009, 27(16): 2622-2629.
16.	García-Sáenz JA, Sastre J, Díaz-Rubio García E. Biomarkers and anti-EGFR therapies for KRAS wild-type metastatic colorectal cancer. Clin Transl Oncol, 2009, 11(11): 737-747.
17.	Mendel DB, Laird AD, Xin X,et al.In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res, 2003, 9(1): 327-337.
18.	Falchook GS, Trent JC, Heinrich MC,et al. BRAF mutant gastrointestinal stromal tumor: first report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance. Oncotarget, 2013, 4(2): 310-315.
19.	Otsuka K, Satoyoshi R, Nanjo H,et al. Acquired intratumoral mutation of KRAS during metastatic progression of colorectal carcinogenesis. Oncol Lett, 2012, 3(3): 649-653.

1. Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet, 2007, 369(9574): 1731-1741.
2. Maleddu A, Pantaleo MA, Nannini M,et al. The role of mutational analysis of KIT and PDGFRA in gastrointestinal stromal tumors in a clinical setting. J Transl Med, 2011, 9: 75.
3. Demetri GD, von Mehren M, Blanke CD,et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med, 2002, 347(7): 472-480.
4. Miettinen M, Lasota J. Histopathology of gastrointestinal stromal tumor. J Surg Oncol, 2011, 104(8): 865-873.
5. Dadzie OE, Yang S, Emley A,et al. RAS and RAF mutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis. Br J Dermatol, 2009, 160(2): 368-375.
6. Agaram NP, Wong GC, Guo T,et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer, 2008, 47(10): 853-859.
7. Agaimy A, Terracciano LM, Dirnhofer S,et al. V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours. J Clin Pathol, 2009, 62(7): 613-616.
8. Miranda C, Nucifora M, Molinari F,et al. KRAS and BRAF mutations predict primary resistance to imatinib in gastrointestinal stromal tumors. Clin Cancer Res, 2012, 18(6): 1769-1776.
9. Daniels M, Lurkin I, Pauli R,et al. Spectrum of KIT/ PDGFRA/BRAF mutations and phosphatidylinositol-3-kinase pathway gene alterations in gastrointestinal stromal tumors (GIST). Cancer Lett, 2011, 312(1): 43-54.
10. Lasota J, Xi L, Coates T, Dennis R,et al. No KRAS mutations found in gastrointestinal stromal tumors (GISTs): molecular genetic study of 514 cases. Mod Pathol, 2013, 26(11): 1488-1491.
11. Fernández-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer, 2011, 2(3): 344-358.
12. Davies H, Bignell GR, Cox C,et al. Mutations of the BRAF gene in human cancer. Nature, 2002, 417(6892): 949-954.
13. Benesova L, Minarik M, Jancarikova D,et al. Multiplicity of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors. Anticancer Res, 2010, 30(5): 1667-1671.
14. Dadzie OE, Yang S, Emley A,et al. RAS and RAF mutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis. Br J Dermatol, 2009, 160(2): 368-375.
15. Loupakis F, Pollina L, Stasi I,et al. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol, 2009, 27(16): 2622-2629.
16. García-Sáenz JA, Sastre J, Díaz-Rubio García E. Biomarkers and anti-EGFR therapies for KRAS wild-type metastatic colorectal cancer. Clin Transl Oncol, 2009, 11(11): 737-747.
17. Mendel DB, Laird AD, Xin X,et al.In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res, 2003, 9(1): 327-337.
18. Falchook GS, Trent JC, Heinrich MC,et al. BRAF mutant gastrointestinal stromal tumor: first report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance. Oncotarget, 2013, 4(2): 310-315.
19. Otsuka K, Satoyoshi R, Nanjo H,et al. Acquired intratumoral mutation of KRAS during metastatic progression of colorectal carcinogenesis. Oncol Lett, 2012, 3(3): 649-653.

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