Significance of tumor heterogeneity of p-Smad2 and c-Met in HER2-positive gastric carcinoma with lymph node metastasis.
Clustering analysis
Gastric cancer
Intra-tumoral heterogeneity
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
01 Jun 2022
01 Jun 2022
Historique:
received:
18
03
2022
accepted:
18
05
2022
entrez:
1
6
2022
pubmed:
2
6
2022
medline:
7
6
2022
Statut:
epublish
Résumé
Tumor heterogeneity has frequently been observed in gastric cancer (GC), but the correlation between patients' clinico-pathologic features and the tumoral heterogeneity of GC-associated molecules is unclear. We investigated the correlation between lymph node metastasis and the intra-tumoral heterogeneity of driver molecules in GC. We retrospectively analyzed the cases of 504 patients who underwent a gastrectomy at the Department of Gastroenterological Surgery, Osaka Metropolitan University and 389 cases drawn from The Cancer Genome Atlas (TCGA) data. We performed a clustering analysis based on eight cancer-associated molecules including HER2, c-Met, and p-Smad2 using the protein expression revealed by our immunohistochemical study of the patients' and TCGA cases. We determined the correlations between HER2 expression and the other molecules based on the degree of lymph node metastasis. Immunohistochemical staining data showed that a 43 of the 504 patients with GC (8.5%) were HER2-positive. In the HER2-positive cases, the expressions of c-Met and p-Smad2 were increased in accord with the lymph-node metastatic level. The overall survival of the HER2-positive GC patients with both p-Smad2 and c-Met expression was significantly (p = 0.030) poorer than that of the patients with p-Smad2-negative and/or c-Met-negative expression. The results of the TCGA data analysis revealed that 58 of the 389 GC cases (14.9%) were ERBB2-positive. MET expression was more frequent in the N1 metastasis group than the N0 group. In the high lymph-node metastasis (N2 and N3) group, SMAD2 expression was more frequent, as was ERBB2 and MET expression. p-Smad2 and c-Met signaling might play important roles in lymph node metastasis in HER2-positive GC.
Sections du résumé
BACKGROUND
BACKGROUND
Tumor heterogeneity has frequently been observed in gastric cancer (GC), but the correlation between patients' clinico-pathologic features and the tumoral heterogeneity of GC-associated molecules is unclear. We investigated the correlation between lymph node metastasis and the intra-tumoral heterogeneity of driver molecules in GC.
MATERIALS AND METHODS
METHODS
We retrospectively analyzed the cases of 504 patients who underwent a gastrectomy at the Department of Gastroenterological Surgery, Osaka Metropolitan University and 389 cases drawn from The Cancer Genome Atlas (TCGA) data. We performed a clustering analysis based on eight cancer-associated molecules including HER2, c-Met, and p-Smad2 using the protein expression revealed by our immunohistochemical study of the patients' and TCGA cases. We determined the correlations between HER2 expression and the other molecules based on the degree of lymph node metastasis.
RESULTS
RESULTS
Immunohistochemical staining data showed that a 43 of the 504 patients with GC (8.5%) were HER2-positive. In the HER2-positive cases, the expressions of c-Met and p-Smad2 were increased in accord with the lymph-node metastatic level. The overall survival of the HER2-positive GC patients with both p-Smad2 and c-Met expression was significantly (p = 0.030) poorer than that of the patients with p-Smad2-negative and/or c-Met-negative expression. The results of the TCGA data analysis revealed that 58 of the 389 GC cases (14.9%) were ERBB2-positive. MET expression was more frequent in the N1 metastasis group than the N0 group. In the high lymph-node metastasis (N2 and N3) group, SMAD2 expression was more frequent, as was ERBB2 and MET expression.
CONCLUSION
CONCLUSIONS
p-Smad2 and c-Met signaling might play important roles in lymph node metastasis in HER2-positive GC.
Identifiants
pubmed: 35650563
doi: 10.1186/s12885-022-09681-3
pii: 10.1186/s12885-022-09681-3
pmc: PMC9161565
doi:
Substances chimiques
SMAD2 protein, human
0
Smad2 Protein
0
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
598Subventions
Organisme : KAKENHI (Grant-in-Aid for Scientific Research)
ID : 18H02883 and 21H03008
Organisme : KAKENHI (Grant-in-Aid for Scientific Research)
ID : 18H02883 and 21H03008
Informations de copyright
© 2022. The Author(s).
Références
Nature. 2003 Oct 9;425(6958):577-84
pubmed: 14534577
Science. 2014 Oct 10;346(6206):256-9
pubmed: 25301631
Nature. 2012 Jun 28;486(7404):537-40
pubmed: 22722843
Mol Cancer Ther. 2012 Mar;11(3):660-9
pubmed: 22238368
Gastric Cancer. 2014;17(3):402-11
pubmed: 23955257
J Mammary Gland Biol Neoplasia. 2011 Jun;16(2):81-8
pubmed: 21590373
PLoS One. 2017 Jun 2;12(6):e0178635
pubmed: 28575019
Oncol Lett. 2021 Jan;21(1):38
pubmed: 33262830
Tumour Biol. 2014 May;35(5):4849-58
pubmed: 24449506
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
BMC Cancer. 2010 Nov 26;10:652
pubmed: 21110833
Oncogene. 2020 May;39(22):4436-4449
pubmed: 32350443
J Pers Med. 2020 Feb 21;10(1):
pubmed: 32098203
Cell Biochem Biophys. 2012 Jan;62(1):221-8
pubmed: 21927816
J Biol Chem. 2004 Jun 4;279(23):24505-13
pubmed: 15044465
Int J Cancer. 2015 Apr 1;136(7):1629-35
pubmed: 25157953
Jpn J Cancer Res. 1997 Feb;88(2):152-9
pubmed: 9119743
Pathol Res Pract. 2020 Nov;216(11):153229
pubmed: 33010699
Nat Genet. 2001 Oct;29(2):117-29
pubmed: 11586292
N Engl J Med. 2012 Mar 8;366(10):883-892
pubmed: 22397650
Ann Oncol. 2016 Jan;27(1):127-33
pubmed: 26489445
J Hum Genet. 2021 Sep;66(9):869-878
pubmed: 33986478
Cancer Res. 2018 Nov 1;78(21):6073-6085
pubmed: 30171053
Histopathology. 2011 Nov;59(5):832-40
pubmed: 22092394
Cancer Res. 2008 Mar 1;68(5):1471-7
pubmed: 18316611
Oncologist. 2018 Sep;23(9):1092-1102
pubmed: 29700210
Eur J Cancer. 2013 Apr;49(6):1448-57
pubmed: 23146959
Nature. 2010 Oct 28;467(7319):1114-7
pubmed: 20981102
World J Gastroenterol. 2013;19(14):2171-8
pubmed: 23599643
J Clin Pathol. 2008 Jan;61(1):89-94
pubmed: 17412870
Virchows Arch. 2019 Mar;474(3):401-402
pubmed: 30506330
Sci Rep. 2021 Feb 25;11(1):4698
pubmed: 33633310