Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a rare presentation of a 66-year-old female with diffuse metastatic adenocarcinoma of unknown primary involving liver, lymphatic system and bone metastases. The neoplastic cells were positive for CK7 and OC125, while negative for CK20, thyroid transcription factor 1, CDX2, BRST-2, chromogranin, synaptophysin, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu). Fluorescence in situ hybridization showed no amplification of the HER2/neu gene. Molecular profiling reported a breast cancer origin with a very high confidence score of 98%. The absence of immunohistochemistry staining for ER, PR, and HER2/neu further classified her cancer as triple-negative breast cancer. Additional studies revealed high expression levels of topoisomerase (Topo) I, androgen receptor, and ribonucleoside-diphosphate reductase large subunit; the results were negative for thymidylate synthase, Topo II-a and O6-methylguanine-DNA methyltransferase. The patient was initially treated with a combination regimen of cisplatin and etoposide, and she experienced a rapid resolution of cancer-related symptoms. Unfortunately, her therapy was complicated by a cerebrovascular accident (CVA), which was thought to be related to cisplatin and high serum mucin. After recovery from the CVA, the patient was successfully treated with second-line chemotherapy based on her tumor expression profile. We highlight the role of molecular profiling in the diagnosis and management of this patient and the implication of personalized chemotherapy in this challenging disease.
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PMID:Occult breast cancer presenting as metastatic adenocarcinoma of unknown primary: clinical presentation, immunohistochemistry, and molecular analysis. 2237 71

The author investigated histopathology of 1,464 consecutive rectal specimens in of our pathology laboratory in Japan. A review of pathological reports was done by computer. Observation of histological slides was performed, when appropriate. The rectal specimens were composed of 1,041 benign lesions and 423 malignant lesions. The 423 malignant lesions were composed of 367 cases of primary rectal carcinoma, 41 cases of carcinoma in adenoma, 7 cases of neuroendocrine tumor, 3 cases of malignant lymphoma, 2 cases of gastrointestinal stromal tumors (GIST), and 3 cases of metastatic carcinoma. Of the 367 cases of primary rectal carcinoma, 37 cases were early carcinomas whose invasion was limited up to the submucosa (early rectal carcinoma). The remaining 330 cases were advanced carcinoma invading beyond the proper muscle layer. The histological types were well differentiated adenocarcinoma in 197 cases, moderately differentiated adenocarcinoma in 129 cases, poorly differentiated adenocarcinoma in 10 cases, mucinous adenocarcinoma in 24 cases, signet ring cell carcinoma in 6 cases, squamous cell carcinoma in 1 case In the 41 cases of carcinoma in adenoma, the carcinoma was well to moderately differentiated adenocarcinoma, and all cases were early carcinomas without invasion or with little invasions to subserosa. The size of carcinoma in adenoma was as follows: < 10 mm, 5 cases; 10-15 mm, 8 cases; 15-20 mm, 23 cases; > 20mm, 5 cases. The background adenoma was as follows: tubular adenoma (n=15), tubulo-villous adenoma (n=14), and villous adenoma (n=12). The 7 cases of neuroendocrine carcinoma consisted of 6 low grade neuroendocrine tumors (carcinoids) and 1 high grade neuroendocrine carcinoma (small cell carcinoma). All were submucosal lesions. Immunohistochemically, the tumor cells were positive for two or more of synaptophysin, chromogranin, neuron-specific enolase, CD56. In small cell carcinoma, KIT and PDGFRA were consistently positive. The 3 cases of malignant lymphoma were diffuse large B-cell lymphomas positive for CD20 and CD79a and negative for NK/T cell markers. The two cases of GIST was spindle cell type, and the risk was intermediate. Kit mutations were recognized in both GISTs. No PDGFRA mutations were seen. Of the 3 metastatic carcinomas, one was a metastasis from prostatic adenocarcinoma, and the remaining two was adenocarcinoma of unknown primary sites.
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PMID:Histopathologic study of the rectum in 1,464 consecutive rectal specimens in a single Japanese hospital: II. malignant lesions. 2341 98

In cancer therapy, the number of drugs targeting cells with characteristic molecular aberrations is continuously rising. However, application of these new drugs still is limited to a few tumor entities. The aim of this study was to test the concept of routinely identifying all possible cancer patients who might eventually benefit from targeted therapy. Therefore, all malignant tumors routinely submitted to our Institute of Pathology over a period of 4 months were brought into a tissue microarray format. Using "in situ" methods, tumors were analyzed for HER2, EGFR, and KIT status as examples for potential therapeutic target genes. In positive cases, target heterogeneity was excluded by analyzing all available large sections. Outside of tumor entities for which targeted drugs are already approved, the study revealed six tumors with homogeneously distributed HER2 overexpression/amplification (bladder, esophageal and colorectal) and seven tumors with homogeneous EGFR amplification (vulvar, ovarian, breast, esophageal and laryngeal, and adenocarcinoma of unknown primary). A total of 151 tumors showed KIT overexpression but none of seven sequenced cases showed KIT mutations. We furthermore report on a 69-year-old patient with homogeneously HER2-amplified metastatic colorectal cancer who is successfully treated by trastuzumab monotherapy. This study demonstrates that tissue microarray based screening for therapeutic target genes in tumors outside established indications represents a feasible approach suitable for routine application. The successful treatment of one patient with homogeneously HER2 positive metastatic colorectal cancer argues for the clinical utility of this approach at least in carefully selected, homogeneous cancers.
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PMID:Continuous tissue microarray based identification of cancers with homogeneous target expression for successful targeted therapy in clinical routine practice. 2431 21

Recently, MET exon 14 deletion (METex14del) has been postulated to be one potential mechanism for MET protein overexpression. We screened for the presence of METex14del transcript by multiplexed fusion transcript analysis using nCounter assay followed by confirmation with quantitative reverse transcription PCR with correlation to MET protein expression by immunohistochemistry (IHC) and MET amplification by fluorescence in situ hybridization (FISH). We extracted RNAs from 230 patients enrolled onto the prospective molecular profiling clinical trial (NEXT-1) (NCT02141152) between November 2013 and August 2014. Thirteen METex14del cases were identified including 3 gastric cancer, 4 colon cancer, 5 non-small cell lung cancer, and one adenocarcinoma of unknown primary. Of these 13 METex14del cases, 11 were MET IHC 3+ and 2 were 2+. Only one out of the 13 METex14del cases was MET amplified (MET/CEP ratio > 2.0). Growths of two (gastric, colon) METex14del+ patient tumor derived cell lines were profoundly inhibited by both MET tyrosine kinase inhibitors and a monoclonal antibody targeting MET. In conclusion, METex14del is a unique molecular aberration present in gastrointestinal (GI) malignancies corresponding with overexpression of MET protein but rarely with MET amplification. Substantial growth inhibition of METex14del+ patient tumor derived cell lines by several MET targeting drugs strongly suggests METex14del is a potential actionable driver mutation in GI malignancies.
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PMID:Gastrointestinal malignancies harbor actionable MET exon 14 deletions. 2637 39