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Gene Expression–Based Predictors of Prognosis and Response to Chemotherapy in Breast Cancer
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Correlating clinical outcome with expression levels yielded many genes from these three studies, and 16 top-performing genes were identified for final model building and validation. Relative expression levels of the 16 genes are measured in relationship to average expression levels of 5 reference genes. While a majority of genes comprising 16 genes are ER (ER, PGR, BCL2, SCUBE2) and proliferation (Ki67, STK15, Survivin, CCNB1, MYBL2) related, there are other genes (HER2, GRB7, MMP11, CTSL2, GSTM1, CD68, BACG1) (9). The unscaled recurrence score (RSu) was calculated with the use of coefficient that are defined on the basis of regression analysis of gene expression. Recurrence score (RS) was rescaled from the unscaled recurrence score (Rsu) as follows: RS = 0 if Rsu < 0; RS = 20 × (Rsu–6.7) if 0 ≤ Rsu ≤ 100; and RS = 100 if Rsu > 100 (9). This resulted in RS ranging from 0 to 100.
Great strides in precision medicine: Personalized oncology and molecular diagnostics
Published in Priya Hays, Advancing Healthcare Through Personalized Medicine, 2017
The Oncotype DX platform utilizes quantitative real-time PCR (RT-qPCR) to analyze the expression of 16 cancer-related genes: Ki67, STK15, survivin, CCNB1, MYBL2, GRB7, HER2, ER, PGR, BCL2, SCUBE2, MMP11, CTSL2, GSTM1, CD68, and BAG1, in addition to five reference genes (ACTB, GAPDH, RPLPO, GUS, and TFRC). Oncotype DX predicts risk of recurrence in ER-positive, lymph node-negative breast cancer patients and provides treatment guidelines via a quantitative system of continuous recurrence score (RS) that ranges between 0 and 100 to predict the risk of recurrence within 10 years. This score has also been shown to be an independent predictor of outcome in multivariate survival analyses. The test utilizes RNA extracted from formalin-fixed paraffin-embedded ER-positive breast cancer samples.
Multiple endocrine neoplasia type 2
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
All the natural downstream targets of RET activation are still unknown despite much work in the last decade. To date, it would appear that activation of RET can result in growth, survival or differentiative signals depending on the downstream pathways triggered, the cell type as well as the developmental stage. Of a total of 18 intracellular tyrosines, all of which are potential phosphorylation sites, 9 have been shown to be phosphorylated as a direct result of RET activation (Liu et al., 1996). Activated (phosphorylated) RET has been shown to interact either directly or indirectly with several adaptor molecules containing src homology (SH2) domains, such as Grb2 (P-Y1096 is the docking site), Grb7 (Y905), Grb 10 (Y905), phospholipase Cγ (Y1015), Crk and Nek and with enigma proteins (Figure 3) (Alberti et al., 1998; Bocciardi et al., 1997; Borrello et al., 1994; Durick et al., 1998b; Murakami et al., 1999a; Pandey et al., 1995).
Selumetinib: the first ever approved drug for neurofibromatosis-1 related inoperable plexiform neurofibroma
Published in Current Medical Research and Opinion, 2021
Sabyasachi Mukhopadhyay, Arpita Maitra, Shouvik Choudhury
These debilitating and painful tumours are characterized by elevated Ras (Rat Sarcoma) and MAPK (mitogen-activated protein kinase) signaling. But therapeutic agents which target the Ras pathway have provided limited responses. The genetic cause of NF1 is mostly due to constitutional heterozygous loss of function mutations of tumor suppressor gene NF1. There is somatic inactivation of wild type allele in Schwann cells of neurofibromas (according to Knudson 2-hits hypothesis). This explains the hyperactivation of RAS MAPK pathway in NF15. NF1 gene encodes a RAS GTPase-activating protein called neurofibromin. It is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies. Multiple downstream pathways (RALGDS, PI3K, RASSF,TIAM1, BRAP2, RIN, GRB7 are involved in RAs signaling. Amongst them only few have been evaluated, in which RAS-MAPK is best studied6. In this condition, selumetinib, an oral inhibitor of MEK (MAPK Kinases)1 and MEK (MAPK Kinases)2 showed response in children with NF1, on the basis of promising activity in adults with several types of advanced-stage cancers7.
An integrative view on breast cancer signature panels
Published in Expert Review of Molecular Diagnostics, 2019
Zhen Wang, Xuanhao Zhang, Shuo Zhang, Xiaofeng Dai
Signatures developed for the same clinical purpose share very few genes (Table 3). This underlines the importance of pathways but not any particular gene or gene combination in driving breast cancer heterogeneity. On the other hand, a few genes occur in multiple signatures for different clinical purposes, which imply the pivotal roles of these genes in the regulatory network driving the clinical differences. For example, MYBL2, BIRC5, ERBB2, Bcl2, and GRB7 are present in both signatures for subtyping and recurrence prognosis (Table 3), suggesting their importance in driving the differential patterns of breast cancer subtypes and cancer relapse.