Receptor tyrosine kinase amplified gastric cancer: Clinicopathologic characteristics and proposed screening algorithm

Cheol Keun Park, Ji Soo Park, Hyo Song Kim, Sun Young Rha, Woo Jin Hyung, Jae Ho Cheong, Sung Hoon Noh, Sang Kil Lee, Yong Chan Lee, Yong min Huh, Hyunki Kim

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR, HER2, and MET using tissue microarrays of 993 AGCs. On IHC, 157 (15.8%) 61, (6.15%), and 85 (8.56%) out of 993 cases scored 2+ or 3+ for EGFR, HER2, and MET, respectively. On SISH, 31.2% (49/157), 80.3% (49/61), and 30.6% (26/85) of 2+ or 3+ cases on IHC showed amplification of the corresponding genes. Of the 993 cases, 104 were classified as RA-GCs. RA-GC status correlated with older age (P < 0.001), differentiated histology (P = 0.001), intestinal or mixed type by Lauren classification (P < 0.001), lymphovascular invasion (P = 0.026), and mutant-pattern of p53 (P < 0.001). The cases were divided into four subgroups using two classification systems, putative molecular classification and histologic-molecular classification, based on Lauren classification, IHC, and SISH results. The histologic-molecular classification showed higher sensitivity for identification of RA-GCs and predicted patient prognosis better than the putative molecular classification. In conclusion, RA-GCs show unique clinicopathologic features. The proposed algorithm based on histologic-molecular classification can be applied to select candidates for genetic examination and targeted therapy.

Original languageEnglish
Pages (from-to)72099-72112
Number of pages14
JournalOncotarget
Volume7
Issue number44
DOIs
Publication statusPublished - 2016 Jan 1

Fingerprint

Receptor Protein-Tyrosine Kinases
Stomach Neoplasms
In Situ Hybridization
Immunohistochemistry
Silver
Gene Amplification
Human Herpesvirus 4
Histology
Guidelines
RNA
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Park, Cheol Keun ; Park, Ji Soo ; Kim, Hyo Song ; Rha, Sun Young ; Hyung, Woo Jin ; Cheong, Jae Ho ; Noh, Sung Hoon ; Lee, Sang Kil ; Lee, Yong Chan ; Huh, Yong min ; Kim, Hyunki. / Receptor tyrosine kinase amplified gastric cancer : Clinicopathologic characteristics and proposed screening algorithm. In: Oncotarget. 2016 ; Vol. 7, No. 44. pp. 72099-72112.
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abstract = "Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR, HER2, and MET using tissue microarrays of 993 AGCs. On IHC, 157 (15.8{\%}) 61, (6.15{\%}), and 85 (8.56{\%}) out of 993 cases scored 2+ or 3+ for EGFR, HER2, and MET, respectively. On SISH, 31.2{\%} (49/157), 80.3{\%} (49/61), and 30.6{\%} (26/85) of 2+ or 3+ cases on IHC showed amplification of the corresponding genes. Of the 993 cases, 104 were classified as RA-GCs. RA-GC status correlated with older age (P < 0.001), differentiated histology (P = 0.001), intestinal or mixed type by Lauren classification (P < 0.001), lymphovascular invasion (P = 0.026), and mutant-pattern of p53 (P < 0.001). The cases were divided into four subgroups using two classification systems, putative molecular classification and histologic-molecular classification, based on Lauren classification, IHC, and SISH results. The histologic-molecular classification showed higher sensitivity for identification of RA-GCs and predicted patient prognosis better than the putative molecular classification. In conclusion, RA-GCs show unique clinicopathologic features. The proposed algorithm based on histologic-molecular classification can be applied to select candidates for genetic examination and targeted therapy.",
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Receptor tyrosine kinase amplified gastric cancer : Clinicopathologic characteristics and proposed screening algorithm. / Park, Cheol Keun; Park, Ji Soo; Kim, Hyo Song; Rha, Sun Young; Hyung, Woo Jin; Cheong, Jae Ho; Noh, Sung Hoon; Lee, Sang Kil; Lee, Yong Chan; Huh, Yong min; Kim, Hyunki.

In: Oncotarget, Vol. 7, No. 44, 01.01.2016, p. 72099-72112.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Receptor tyrosine kinase amplified gastric cancer

T2 - Clinicopathologic characteristics and proposed screening algorithm

AU - Park, Cheol Keun

AU - Park, Ji Soo

AU - Kim, Hyo Song

AU - Rha, Sun Young

AU - Hyung, Woo Jin

AU - Cheong, Jae Ho

AU - Noh, Sung Hoon

AU - Lee, Sang Kil

AU - Lee, Yong Chan

AU - Huh, Yong min

AU - Kim, Hyunki

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