Increased gene copy number of KIT and VEGFR2 at 4q12 in primary breast cancer is related to an aggressive phenotype and impaired prognosis

Abstract

Triple-negative breast cancer (TNBC) is associated with poor prognosis and no targeted treatments are available for TNBC. Drugs inhibiting tyrosine kinases, such as vascular endothelial growth factor receptor 2 (VEGFR2) and KIT, have shown some promising results for patients with TNBC. The aim of the study was to investigate whether gains and/or amplifications of VEGFR2 and KIT, located at 4q12, occur in TNBC. Fluorescence in situ hybridization (FISH) was used to quantify gene copy numbers of VEGFR2 and KIT in 83 primary human breast cancers including 31 TNBCs. Gains were defined as ≥ 4 gene copies in >40% of the cancer cells, whereas amplification was defined as CEP >2 in more than 10% of the cancer cells. A tumor was considered FISH positive for KIT and/or VEGFR2 if it displayed copy number gain and/or amplification. Ten (32%) of the TNBCs were VEGFR2 FISH positive and nine (29%) were KIT FISH positive, whereas non-TNBCs were FISH positive for VEGFR2 and KIT in nine (18%) cases for both genes, but no significant difference between TNBCs and non-TNBCs was found. FISH positivity for VEGFR2 and KIT was significantly correlated (χ(2) test, P < 0.001), and significantly related to ER negativity and high Nottingham histological grade (NHG). A significantly worse 5-year breast cancer specific survival (BCSS) was seen for FISH positive cases. Increased copy number of VEGFR2 and KIT thus has the potential of functioning as a novel predictive biomarker for selected targeted therapy particularly in the difficult-to-treat TNBC patient category.

The Three Receptor Tyrosine Kinases c-KIT, VEGFR2 and PDGFRα, Closely Spaced at 4q12, Show Increased Protein Expression in Triple-Negative Breast Cancer

“…In a recent study, an increased copy number of the genes c-KIT and VEGFR2 was found in the TNBC subgroup, and increased gene copy number was related to an aggressive phenotype and impaired prognosis [27]. These results were not confirmed in this study.…”

“…Any tissue sample containing ≥5 cells with gains and/or amplifications was considered FISH positive. The cut-off point for FISH positivity was chosen based on a comparison of cut-off points used in recent similar studies [20], [21], [27], [37]. Since in this study TMAs of formalin-fixed tissue were used, we used the cut-off point that was closest to the one used by Joensuu et al [20] who used the same type of tissue material.…”

“…A previous study has shown that increased gene copy number of c-KIT and VEGFR2 in primary breast cancer is related to an aggressive phenotype and impaired prognosis [27].…”

Molecular profiling, including TERT promoter mutations, of acral lentiginous melanomas

“…Besides these two oncogenes, this locus also harbors another important oncogene, KDR, also known as VEGFR2 (vascular endothelial growth factor receptor-2 gene) [21,22]. Importantly, many of the mutated molecules in ALM have emerged for therapeutic targets, such as BRAF, KIT/ PDGFR, and VEGFR2 [23][24][25].…”

Pairwise shared genomic segment analysis in three Utah high-risk breast cancer pedigrees

“…In addition, our region includes cytogenetic band 4q12 which has previously been proposed as a location potentially harboring genes important in breast cancer development because of observed loss of heterozygosity at 4q12 in both BRCA1/2 and sporadic breast cancer tumors [21,22]. Furthermore, there has been recent interest in two candidate genes in this region, with increased gene copy number for genes KIT and VEGFR2 found in triple negative breast cancer, an aggressive and difficult to treat form of the disease [23]. Our region on chromosome 14q includes the breast cancer candidate gene RAD51L1 , which contains one of the two most significant associations reported in a multi-stage genomewide association study of 9,770 cases and 10,799 controls [24].…”