Table 1.
List of mutations discovered in TEMPUS testing in retroperitoneal adenocarcinoma with associated VAF and proposed mechanism.
| Gene | Function | Variant | Variant allele fraction (VAF) | Possible mechanism |
|---|---|---|---|---|
| ATP7B | Copper-transporting ATPase 2 protein; export of copper out of cells | c.4232G>A p.R1411Q Missense variant NM_000053 |
61.5% | Increased platinum efflux out of cancer cells(17) |
| ERCC2 | DNA helicase protein; nucleotide excision repair (NER) pathway | c.491A>G p.H164R Missense variant NM_000400 |
54.9% | Enhanced DNA repair(17) Cisplatin-induced DNA damage involves the formation of platinum-DNA adducts. The NER pathway is responsible for removal of these bulky adducts. Higher levels of ERCC2 promotes resistance by preventing cisplatin-induced DNA damage and apoptosis of cancer cells. (18) |
| CTNNA1 | Catenin alpha-1; cell adhesion process | c.839A>G p.Y280C Missense variant NM_001903 |
49.9% | No association with cisplatin resistance found |
| HIF1A | Hypoxia-inducible factor 1 subunit alpha; master transcriptional regulator of the adaptive response to hypoxia | c.1292C>T p.T431I Missense variant NM_001243084 |
46.4% | Indirectly via upregulation of the expression of platinum resistance related genes: such as signaling genes, DNA repair enzymes, drug efflux transporters, and EMT transcription factors. (17) Increases glycolysis and acidic waste production, which results in increased multidrug transporter expression and cisplatin resistance. Knockdown of HIF-1a reduces cisplatin resistance by redirecting aerobic glycolysis in resistant cancer cells towards mitochondrial oxidative phosphorylation, leading to cell death through overproduction of reactive oxygen species (ROS). (19) |
| RAD21 | Cohesin complex component; Double-strand DNA break repair | c.1349G>A p.R450H Missense variant NM_006265 |
40.2% | Enhanced DNA repair. (17) As an important protein involved in the process of homologous recombination DNA repair, RAD21 reduces cisplatin-induced double strand DNA damage and cancer cell apoptosis. (20) |
| EP300 | E1A binding protein p300; histone acetyltransferase; regulates transcription via chromatin remodeling; Increases activity of p53; HIF1A co-activator. | c.410G>C p.G137A Missense variant NM_001429 |
34.5% | Prevention of epithelial-to-mesenchymal transition (EMT). EMT is an important step in cancer metastasis involving the loss of E-Cadherin and increased ability to degrade the extracellular matrix and invade other tissues. EMT also generates cancer cells with stem cell-like characteristics. Transcriptional activators of E-Cadherin, such as EP300, help prevent EMT and maintain the cell in an epithelial state. The loss of EP300 is thought to allow for initiation of EMT, generation of cancer stem cells, and thus contribute to drug resistance.(21) |
| ABCC3 | Canalicular multispecific organic anion transporter 2; | c.1975G>A p.V659M Missense variant NM_003786 |
27.6% | Increased platinum efflux out of cancer cells(17) |
| BCLAF1 | BCL2 associated transcription factor 1; transcriptional repressor; overexpression induces apoptosis | c.472A>G p.R158G Missense variant NM_014739 |
16.0% | No association with cisplatin resistance found |
| NSD1* | Nuclear receptor binding SET domain protein 1; enhances androgen receptor transactivation | c.661G>A p.A221T Missense variant NM_022455 |
15.0% (retroperitoneal adenocarcinoma) 15.0% (liver adenocarcinoma) |
Wnt/β-catenin signaling; inhibits apoptosis in cancer cells(17) Overexpression of NSD1 promotes accumulation of β-catenin in the nucleus, which is thought to promote the upregulation of oncogenes, such as c-Myc and cyclin D1. (22) |
| SEMA3C | Semaphorin 3C; | c.1583G>A p.R528Q Missense variant NM_006379 |
13.4% | Sema3C enhances invasion and facilitates stem cell marker expression via the upregulation of EMT, conferring drug resistance.(17, 23) |
| FLT1* | FMS related receptor tyrosine kinase 1; member of VEGF family; growth factor signaling | c.3901A>T p.S1301C Missense variant NM_002019 |
12.9% (retroperitoneal adenocarcinoma) 20.6% (liver adenocarcinoma) |
No association with cisplatin resistance found |
| TET2* | Methylcytosine dioxygenase; chromatin remodeling; DNA demethylation | c.3748G>A p.E1250K Missense variant NM_001127208 |
12.1% (retroperitoneal adenocarcinoma) 17.3% (liver adenocarcinoma) |
Loss of TET2 leads to DNA hypermethylation at enhancer elements, silencing of tumor suppressor genes, and drug resistance.36 TET2 causes transcriptional repression of IL-6, an important inflammatory mediator in the tumor microenvironment. Increased levels of IL-6 have been shown to promote multi-drug resistance by activating various pathways implicated in cell cycle regulation and proliferation.(17, 24) |
*Found in both retroperitoneal adenocarcinoma and liver adenocarcinoma.