This product has been obsoleted by our more Comprehensive Thyroid Lung (CTL) Kit . We will continue to provide this kit to our validated customers.
The FusionPlex Lung Thyroid Kit is a targeted sequencing assay that simultaneously detects and characterizes fusions of 8 genes associated with NSCLC and thyroid cancer. Using proprietary Anchored Multiplex PCR (AMP™)-based enrichment, fusions of all genes in this kit can be identified in a single sequencing assay without prior knowledge of their fusion partners.
For Research Use Only. Not for use in diagnostic procedures.
The Venn diagram above shows the NSCLC- and thyroid cancer-specific targets and indicates the genes that overlap both diseases.
|ALK||NM_004304||19, 20, 21, 22||5'||Fusion|
|ROS1||NM_002944.2||31, 32, 33, 34, 35, 36, 37||5'||Fusion|
|RET||NM_020975.4||8, 9, 10, 11, 12, 13||5'||Fusion|
|FGFR3||NM_000142||16, 17, intron 18||3'||Fusion|
|PPARG||NM_005037.5||1, 2, 3||5'||Fusion|
|NTRK1||NM_001007792||8, 10, 11, 12, 13||5'||Fusion|
|NTRK3||NM_002530||13, 14, 15, 16||5'||Fusion|
|MET||NM_000245||15 (detects exon 14 skipping)||5'||N/A|
Lung cancer is the most deadly form of cancer in the United States and the third most-diagnosed cancer (1). The major types of lung cancer are non-small cell lung cancer and small cell lung cancer.
Lung cancer has the highest mortality rate and third highest incidence rate in the United States (1).
Non-small cell lung cancer (NSCLC) is much more common than small cell lung cancer, accounting for 85% of all lung cancer cases (2). The survival rate for NSCLC cases varies based on the stage at diagnosis, but the average 5-year survival rate is 15.7% (3). Although NSCLC is often associated with smoking, the subtype is also the most common form in non-smokers and can be attributed to genetic alterations beyond single nucleotide polymorphisms, including fusion mutations (4, 5).
NSCLC is stratified into 3 subtypes based on phenotypic and genotypic differentiation (2, 6).
Adenocarcinoma is the most common form of NSCLC (40% of lung cancers) (5). Like all lung cancers, this subtype is often linked to smoking, although it is not uncommon for non-smokers to develop this subtype of the disease. Gene fusions associated with NSCLC include but are not limited to ALK, RET, ROS1, FGFR3 and NTRK1. Alternative c-MET splicing leading to exon 14 skipping has also been demonstrated to be oncogenic in adenocarcinomas (7).
Squamous cell carcinoma makes up 25-30% of all lung cancers and is usually linked to smoking (5). FGFR3 mutations have been detected in this NSCLC type (8).
Large cell carcinoma comprises 10-15% of lung cancers (5).
Other types of lung cancer include small cell lung cancer and large carcinoid tumor cancer, making up 10-15% and less than 5% of lung cancers, respectively. They also vary in their rate of progression to metastatic disease, with the former spreading quickly and the latter spreading slowly (5).
The FusionPlex Lung Thyroid Kit includes primers to detect the following lung cancer-associated targets:
ALK fusions predominate the list of lung cancer-associated fusions. In clinical trials, patients that harbored these fusions displayed greater than 60% radiographic response rate when treated with the tyrosine kinase inhibitor (TKI) crizotinib (9). Also, progression-free survival with crizotinib treatment exceeded that of the standard chemotherapy treatment (7.7 months vs. 3.0 months, respectively) (10).
Oncogenic ROS1 rearrangements tend to strike significantly younger patients and is more likely with those who have not smoked (11). In a phase I trial, ROS1-positive NSCLC cases treated with crizotinib exhibited a 72% response rate (12).
RET rearrangements have been reported to convey some level of responsiveness to TKI (cabozantinib) therapy (13). In in vitro models with KIF5B-RET fusions, vandetanib inhibited cell proliferation (14).
In an initial report from a phase II trial with a RET TKI and with prospective RET testing, RET fusion positivity conveyed partial response or disease control with cabozantinib (13, 14). In the clinic, KIF5B-RET fusion-positive lung adenocarcinomas were responsive to vandetanib (15).
Recent work analyzing 576 adenocarcinomas found the FGFR3-TACC2 fusion in a subset (0.5%) of the samples (8). FGF receptors are currently a popular target in drug discovery and development, and FGFR3 fusions have been suggested for targeting using FGFR inhibitors in clinical trials (8).
A recent study reported that 3 out of 91 (3.3%) of adenocarcinomas carried NTRK1 fusions. In pre-clinical in vitro studies, NTRK1 inhibition causes growth inhibition in a NTRK-fusion positive cell line. In the clinic, crizotinib treatment showed limited efficacy (16).
The c-Met receptor tyrosine kinase is involved in tumorigenesis, cell motility, scattering, invasion and metastasis and has been implicated in small cell lung cancer. Somatic rearrangements have been shown to lead to mutations resulting in the loss of the entire juxtamembrane domain (exon 14) of c-MET (17).
Thyroid cancer is the most common endocrine cancer, and although the incidence rate of this disease has increased more rapidly than any other cancer type in the United States, the mortality rate has not followed the same trend [see graph below] (18). Indeed, the disease has an average 5-year survival rate of 97.8% (19). This divergence between incidence and mortality rates is thought to be due to improvements in neoplasm detection techniques, risk factor exposure variations and disease diagnostic and treatment strategies (20).
Thyroid cancer incidence rates have increased in the last 30 years, while mortality rates remain unchanged (18).
The majority of malignant thyroid cancers are differentiated cancers derived from thyroid follicular cells. These differentiated cancers are stratified into subtypes that have different phenotypic and genotypic characteristics, with most thyroid carcinomas containing one of a small number of mutually exclusive driver mutations (21).
Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, comprising 70-80% of all thyroid cancers. This subtype is often associated with radiation exposure, which gives rise to both genomic rearrangements and point mutations(22, 23) . Gene fusions related to PTC include RET, NTRK1 and NTRK3(23-25).
Follicular thyroid cancer is another differentiated cancer type that comprises 10-15% of all thyroid cancers. PPARG fusions are prominent in follicular TC (19).
Medullary and anaplastic cancers make up less than 15% of all thyroid cancers and are not often associated with gene fusions (19).
The FusionPlex Lung Thyroid Kit includes primers to detect the following thyroid cancer-associated targets:
Approximately 10–20% of sporadic papillary thyroid cancers harbor RET fusions. The prevalence of RET rearrangements is higher in patients with a history of radiation exposure (50–80%) and in young adult and pediatric populations (40–70% (26). Multiple RET rearrangements have been described in PTCs, but the following rearrangements are most common:
NTRK1 fusions are commonly found in papillary thyroid cancer. Three genes known to be involved in these genomic rearrangements are TPM3, TPR and TFG. All three of these fusions can lead to an oncogenic protein that is constitutively active in the binding of NGF? leading to constant cell division (25).
A recent study examining papillary thyroid carcinomas from a cohort of post-Chernobyl Ukrainian-Americans detected genomic rearrangements in 9 of 62 cases. The most common rearrangement was ETV6-NTRK3 (24).
The fusion transcript PAX8-PPARG is found in 35% of follicular thyroid carcinomas and is present to a lesser degree in a subset of follicular variant or PTC (21, 30). Recent studies suggest that PAX8-PPARG fusions activate Wnt/TCF signaling via the DNA binding domain of PPARG resulting in increased invasiveness and anchorage-independent growth in mouse models (30). Also, the fusion transcript CREB3L2-PPARG was recently detected and has been estimated to occur in less than 3% of thyroid follicular carcinomas (31).
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