Amplification of growth factor receptor genes and DNA ploidy pattern in the progression of gastric cancer

Abstract

To study the background of oncogene amplification in gastric cancers, we examined the correlation between occurrence of oncogene amplification and DNA ploidy pattern. In 57 primary gastric cancers, amplifications of c-erbB, c-erbB-2, c-met and K-sam genes were investigated by Southern blot analysis, and the DNA ploidy pattern was determined by static cytofluorometry and by flow cytometry. Oncogene amplification was detected in 11 cancers, 10 of which were advanced gastric cancers and 1 was an early differentiated type. The amplification of c-erbB-2 and K-sam genes was found exclusively in differentiated- and undifferentiated-type cancers, respectively. Of the 11 cancers, 5 were DNA-diploid and 6 were DNA-aneuploid. All the 11 tumours with oncogene amplification contained polyploid cell populations (polyploidy), whereas none of the tumours without polyploidy showed oncogene amplification. In differentiated-type cancers the incidence of polyploidy was high in both early and advanced stages, while in undifferentiated-type cancers it was low in early stages but significantly higher in advanced stages. It was shown that amplification of growth factor receptor genes is closely related to the presence of polyploidy, irrespective of any different stemline DNA-ploidy mode. The time-course of oncogene amplification and kinds of genes amplified may differ between differentiated- and undifferentiated-type gastric cancers.

RON(MST1R)is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

“…71 Tumor samples confirmed to have high MET and MST1R GCN by FISH revealed that the adjacent histologically normal mucosa were disomic by FISH, supporting the notion that chromosomal instability and the development of polysomy is associated with histologic progression of disease. 72 The correlation of histologic tumor progression that we observed with increasing GCN of MST1R and MET through polysomy is consistent with a previous report correlating histologic progression and worse outcome of patients with nonrandom chromosome 3 gain in GEC. 72 Tissue p9 showed patchy areas of MET gene amplification that correlated with very high protein expression by IHC in the primary tumor (particularly the invasive front), whereas other areas of tumor only showed high polysomy and lower MET expression levels.…”

“…72 The correlation of histologic tumor progression that we observed with increasing GCN of MST1R and MET through polysomy is consistent with a previous report correlating histologic progression and worse outcome of patients with nonrandom chromosome 3 gain in GEC. 72 Tissue p9 showed patchy areas of MET gene amplification that correlated with very high protein expression by IHC in the primary tumor (particularly the invasive front), whereas other areas of tumor only showed high polysomy and lower MET expression levels. Moreover, the metastatic lymph node for this same patient showed MET amplification in all of the tumor cells when evaluated by FISH, again supporting the notion of clonal evolution and selection for metastatic capability.…”

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

“…FGFR2 is amplified in 4% of breast cancers (5,8), 3% to 25% of gastric cancers (9)(10)(11)(12) and in colon cancer (13,14). In addition, activating mutations in FGFR2 and FGFR3 have been found in 10% of endometrial cancers (15)(16)(17) and about 60% of nonmuscle-invasive bladder tumors (18,19), respectively.…”

MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas

“…1,4 As mutations in the kinase domain of MET gene are almost lacking in gastric carcinomas, 5 its activation has been mostly attributed to gene amplification. [6][7][8] Although earlier Japanese reports described MET gene amplification in approximately 20% of gastric cancers by comparative genomic in situ hybridization or southern blot analysis, [9][10][11][12][13] recent FISH analyses showed rare or no amplification in locally advanced gastric carcinomas. 3,14 MET activation through copy number gain measured by quantitative real-time PCR, 3,7,8,14,15 FISH 6,14 or silver in situ hybridization, 16 and protein overexpression assessed by immunohistochemistry have been reported in gastric carcinomas.…”