Unraveling the spectrum of KIT mutations in gastrointestinal stromal tumors: An Indian Tertiary Cancer Center Experience

Trupti Pai; Munita Bal; Omshree Shetty; Mamta Gurav; Vikas Ostwal; Anant Ramaswamy; Mukta Ramadwar; Sangeeta Desai

doi:10.4103/sajc.sajc_275_16

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ORIGINAL ARTICLE : GI Cancer

06 (

); 113-117

doi:

10.4103/sajc.sajc_275_16

Unraveling the spectrum of KIT mutations in gastrointestinal stromal tumors: An Indian Tertiary Cancer Center Experience

Trupti Pai¹, Munita Bal², Omshree Shetty^1,, Mamta Gurav¹, Vikas Ostwal³, Anant Ramaswamy³, Mukta Ramadwar², Sangeeta Desai^1,2

1 Division of Molecular Pathology, Tata Memorial Centre, Mumbai, Maharashtra

2 Department of Pathology, Tata Memorial Centre, Mumbai, Maharashtra

3 Department of Medical Oncology, Tata Memorial Centre, Mumbai, Maharashtra

*Corresponding author: Dr. Omshree Shetty. omshreens@gmail.com

Published: 2020-12-22

MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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Abstract

Background: Primary mutations in the KIT gene are the driving force for gastrointestinal stromal tumors (GIST) tumorigenesis. Predictive role of KIT mutation status aids oncologists in patient management. There is a paucity of comprehensive data on the frequency of mutations in the KIT gene in GIST affecting Indian patients. The aims of this study were to determine the frequency and spectrum of molecular alterations affecting the KIT gene and assess their association with clinicopathologic features in a cohort of patients of GIST. Materials and Methods: Morphological and immunohistochemically confirmed GIST cases (n = 114) accessioned from August 2014-June 2015 were analyzed for mutations in KIT exons 9, 11, 13, and 17 and subjected to Sanger sequencing onto the ABI 3500 Genetic Analyzer. The sequences were analyzed using sequence analysis software: SeqScape^® and Chromas Lite. Results:KIT mutations were seen in 70% of cases and the majority of KIT mutations involved exon 11 (57%), followed by exon 9 (10%), exon 13 (3%), and exon 17 (1%). Most common exon 11 mutations were in-frame deletions (61.4%) followed by substitution mutations (19.3%). Exon 9 mutations showed identical duplication of Ala-Tyr at codons 502–503. Simultaneous mutations affecting exon 11 and 13 were discovered. Novel variations, namely, p.Q556E (c.1666C>G), p.Q556dup (c.1666_1668dupCAG), p.K558_V559delinsS (c.1672_1677delAAGGTTinsAGT), p.Y503_F504insTY (c.1509_1510insACCTAT), and p.K642R (c.1925A>G) involving exons 11, 9, and 13, respectively, were observed. Interpretation and Conclusions: First study with complete analysis of all 4 exons of KIT (exons 9, 11, 13, and 17) in Indian GIST patients. Along with well-described KIT mutations, several rare double mutations as well as novel alterations were reported in this series.

Keywords

Acknowledgment

The support from Molecular Pathology, Surgical Pathology and Medical Oncology GI Unit is acknowledged.

References

ESMO/European Sarcoma Network Working Group. Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25 Suppl 3:iii21-6.
Corless CL. Gastrointestinal stromal tumors: What do we know now? Mod Pathol 2014;27 Suppl 1:S1-16.
Lasota J, Miettinen M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol 2006;23:91-102.
Andersson J, Bümming P, Meis-Kindblom JM, Sihto H, Nupponen N, Joensuu H, et al. Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology 2006;130:1573-81.
Ahmad F, Lad P, Bhatia S, Das BR. Molecular spectrum of c-KIT and PDGFRA gene mutations in gastro intestinal stromal tumor: Determination of frequency, distribution pattern and identification of novel mutations in Indian patients. Med Oncol 2015;32:424.
Yamamoto H, Oda Y, Kawaguchi K, Nakamura N, Takahira T, Tamiya S, et al. c-KIT and PDGFRA mutations in extragastrointestinal stromal tumor (gastrointestinal stromal tumor of the soft tissue). Am J Surg Pathol 2004;28:479-88.
Foo WC, Liegl-Atzwanger B, Lazar AJ. Pathology of gastrointestinal stromal tumors. Clin Med Insights Pathol 2012;5:23-33.
Sen A, Gangavatiker R. EXON 11, C KIT mutation in a 'CD 117' & 'DOG 1' negative colonic gastrointestinal tumor. Med J Armed Forces India 2014;70:186-8.
Cyriac S, Rajendranath R, Sagar TG. Gastrointestinal stromal tumor: Analysis of outcome and correlation with c-KIT status in Indian population. Indian J Cancer 2014;51:35-9.
Ramaswamy A, Ostwal V, Shetty O, Sahu A, Paul D, Pai T, et al. Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumours, will KIT mutation analysis be a pathfinder? J Gastrointest Cancer 2016;47:381-8.
Ramaswamy A, Pande N, Shetty O, Shetty N, Gupta S, Ostwal V. Pazopanib in metastatic multiply treated progressive gastrointestinal stromal tumors: Feasible and efficacious. J Gastrointest Oncol 2016;7:638-43.
Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC; 2010.
Debiec-Rychter M, Dumez H, Judson I, Wasag B, Verweij J, Brown M, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689-95.
Wasag B, Debiec-Rychter M, Pauwels P, Stul M, Vranckx H, Oosterom AV, et al. Differential expression of KIT/PDGFRA mutant isoforms in epithelioid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site. Mod Pathol 2004;17:889-94.
Kern A, Görgens H, Dittert DD, Krüger S, Richter KK, Schackert HK, et al. Mutational status of KIT and PDGFRA and expression of PDGFRA are not associated with prognosis after curative resection of primary gastrointestinal stromal tumors (GISTs). J Surg Oncol 2011;104:59-65.
Tryggvason G, Hilmarsdottir B, Gunnarsson GH, Jónsson JJ, Jónasson JG, Magnússon MK. Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in Iceland. APMIS 2010;118:648-56.
Kang HJ, Nam SW, Kim H, Rhee H, Kim NG, Kim H, et al. Correlation of KIT and platelet-derived growth factor receptor alpha mutations with gene activation and expression profiles in gastrointestinal stromal tumors. Oncogene 2005;24:1066-74.
Teong YT, Teo ST, Tan LP, Wu BQ, Peh SC. An immunohistochemical and molecular study of gastrointestinal stromal tumours. Med J Malaysia 2006;61:526-33.
Du CY, Shi YQ, Zhou Y, Fu H, Zhao G. The analysis of status and clinical implication of KIT and PDGFRA mutations in gastrointestinal stromal tumor (GIST). J Surg Oncol 2008;98:175-8.
Emile JF, Brahimi S, Coindre JM, Bringuier PP, Monges G, Samb P, et al. Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs. Med Oncol 2012;29:1765-72.
Baker G, Babb C, Schnugh D, Nayler S, Louw M, Goedhals J, et al. Molecular characterisation of gastrointestinal stromal tumours in a South African population. Oncol Lett 2013;5:155-60.
Saponara M, Urbini M, Astolfi A, Indio V, Ercolani G, Del Gaudio M, et al. Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRa genotype evaluated by next generation sequencing (NGS). Oncotarget 2015;6:42243-57.
Ricci R, Martini M, Cenci T, Antinori A, Cassano A, Larocca LM. Case of rectal GI stromal tumor demonstrating that KIT and PDGFRA mutations are not always mutually exclusive. J Clin Oncol 2016;34:e107-9.
Lee JH, Zhang X, Jung WY, Chae YS, Park JJ, Kim I. DNA ploidy and C-KIT mutation in gastrointestinal stromal tumors. World J Gastroenterol 2004;10:3475-9.
Sakurai S, Oguni S, Hironaka M, Fukayama M, Morinaga S, Saito K. Mutations in c-KIT gene exons 9 and 13 in gastrointestinal stromal tumors among Japanese. Jpn J Cancer Res 2001;92:494-8.
Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006;24:4764-74.
Lasota J, vel Dobosz AJ, Wasag B, Wozniak A, Kraszewska E, Michej W, et al. Presence of homozygous KIT exon 11 mutations is strongly associated with malignant clinical behavior in gastrointestinal stromal tumors. Lab Invest 2007;87:1029-41.
Lasota J, Dansonka-Mieszkowska A, Stachura T, Schneider-Stock R, Kallajoki M, Steigen SE, et al. Gastrointestinal stromal tumors with internal tandem duplications in 3' end of KIT juxtamembrane domain occur predominantly in stomach and generally seem to have a favorable course. Mod Pathol 2003;16:1257-64.

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[1] ESMO/European Sarcoma Network Working Group. Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25 Suppl 3:iii21-6.

[2] Corless CL. Gastrointestinal stromal tumors: What do we know now? Mod Pathol 2014;27 Suppl 1:S1-16.

[3] Lasota J, Miettinen M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol 2006;23:91-102.

[4] Andersson J, Bümming P, Meis-Kindblom JM, Sihto H, Nupponen N, Joensuu H, et al. Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology 2006;130:1573-81.

[5] Ahmad F, Lad P, Bhatia S, Das BR. Molecular spectrum of c-KIT and PDGFRA gene mutations in gastro intestinal stromal tumor: Determination of frequency, distribution pattern and identification of novel mutations in Indian patients. Med Oncol 2015;32:424.

[6] Yamamoto H, Oda Y, Kawaguchi K, Nakamura N, Takahira T, Tamiya S, et al. c-KIT and PDGFRA mutations in extragastrointestinal stromal tumor (gastrointestinal stromal tumor of the soft tissue). Am J Surg Pathol 2004;28:479-88.

[7] Foo WC, Liegl-Atzwanger B, Lazar AJ. Pathology of gastrointestinal stromal tumors. Clin Med Insights Pathol 2012;5:23-33.

[8] Sen A, Gangavatiker R. EXON 11, C KIT mutation in a 'CD 117' & 'DOG 1' negative colonic gastrointestinal tumor. Med J Armed Forces India 2014;70:186-8.

[9] Cyriac S, Rajendranath R, Sagar TG. Gastrointestinal stromal tumor: Analysis of outcome and correlation with c-KIT status in Indian population. Indian J Cancer 2014;51:35-9.

[10] Ramaswamy A, Ostwal V, Shetty O, Sahu A, Paul D, Pai T, et al. Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumours, will KIT mutation analysis be a pathfinder? J Gastrointest Cancer 2016;47:381-8.

[11] Ramaswamy A, Pande N, Shetty O, Shetty N, Gupta S, Ostwal V. Pazopanib in metastatic multiply treated progressive gastrointestinal stromal tumors: Feasible and efficacious. J Gastrointest Oncol 2016;7:638-43.

[12] Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC; 2010.

[13] Debiec-Rychter M, Dumez H, Judson I, Wasag B, Verweij J, Brown M, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689-95.

[14] Wasag B, Debiec-Rychter M, Pauwels P, Stul M, Vranckx H, Oosterom AV, et al. Differential expression of KIT/PDGFRA mutant isoforms in epithelioid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site. Mod Pathol 2004;17:889-94.

[15] Kern A, Görgens H, Dittert DD, Krüger S, Richter KK, Schackert HK, et al. Mutational status of KIT and PDGFRA and expression of PDGFRA are not associated with prognosis after curative resection of primary gastrointestinal stromal tumors (GISTs). J Surg Oncol 2011;104:59-65.

[16] Tryggvason G, Hilmarsdottir B, Gunnarsson GH, Jónsson JJ, Jónasson JG, Magnússon MK. Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in Iceland. APMIS 2010;118:648-56.

[17] Kang HJ, Nam SW, Kim H, Rhee H, Kim NG, Kim H, et al. Correlation of KIT and platelet-derived growth factor receptor alpha mutations with gene activation and expression profiles in gastrointestinal stromal tumors. Oncogene 2005;24:1066-74.

[18] Teong YT, Teo ST, Tan LP, Wu BQ, Peh SC. An immunohistochemical and molecular study of gastrointestinal stromal tumours. Med J Malaysia 2006;61:526-33.

[19] Du CY, Shi YQ, Zhou Y, Fu H, Zhao G. The analysis of status and clinical implication of KIT and PDGFRA mutations in gastrointestinal stromal tumor (GIST). J Surg Oncol 2008;98:175-8.

[20] Emile JF, Brahimi S, Coindre JM, Bringuier PP, Monges G, Samb P, et al. Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs. Med Oncol 2012;29:1765-72.

[21] Baker G, Babb C, Schnugh D, Nayler S, Louw M, Goedhals J, et al. Molecular characterisation of gastrointestinal stromal tumours in a South African population. Oncol Lett 2013;5:155-60.

[22] Saponara M, Urbini M, Astolfi A, Indio V, Ercolani G, Del Gaudio M, et al. Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRa genotype evaluated by next generation sequencing (NGS). Oncotarget 2015;6:42243-57.

[23] Ricci R, Martini M, Cenci T, Antinori A, Cassano A, Larocca LM. Case of rectal GI stromal tumor demonstrating that KIT and PDGFRA mutations are not always mutually exclusive. J Clin Oncol 2016;34:e107-9.

[24] Lee JH, Zhang X, Jung WY, Chae YS, Park JJ, Kim I. DNA ploidy and C-KIT mutation in gastrointestinal stromal tumors. World J Gastroenterol 2004;10:3475-9.

[25] Sakurai S, Oguni S, Hironaka M, Fukayama M, Morinaga S, Saito K. Mutations in c-KIT gene exons 9 and 13 in gastrointestinal stromal tumors among Japanese. Jpn J Cancer Res 2001;92:494-8.

[26] Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006;24:4764-74.

[27] Lasota J, vel Dobosz AJ, Wasag B, Wozniak A, Kraszewska E, Michej W, et al. Presence of homozygous KIT exon 11 mutations is strongly associated with malignant clinical behavior in gastrointestinal stromal tumors. Lab Invest 2007;87:1029-41.

[28] Lasota J, Dansonka-Mieszkowska A, Stachura T, Schneider-Stock R, Kallajoki M, Steigen SE, et al. Gastrointestinal stromal tumors with internal tandem duplications in 3' end of KIT juxtamembrane domain occur predominantly in stomach and generally seem to have a favorable course. Mod Pathol 2003;16:1257-64.

Unraveling the spectrum of KIT mutations in gastrointestinal stromal tumors: An Indian Tertiary Cancer Center Experience

Abstract

Abstract

Keywords

Acknowledgment

References

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