Prognosis and behavior. Certain genetic alterations are associated with a poor prognosis, and thus the presence of these alterations determines the patient’s subsequent therapy. FISH and PCR methods can be used to detect amplification of oncogenes such as HER2 and NMYC, which provide therapeutic and prognostic information for breast cancers and neuroblastomas, respectively. Sequencing of cancer genomes is now routine in some centers, allowing for the identification of point mutations in cancer genes such as TP53 that predict a poor outcome in many different types of cancer. Although not yet standard of care, efforts are ongoing to develop tests that assess the host immune response to tumors, for example, by quantifying the number of infiltrating cytotoxic T cells, as this too is helpful in gauging prognosis.
Detection of minimal residual disease. Another emerging use of molecular techniques is for detection of minimal residual disease after treatment. For example, detection of BCR-ABL transcripts by PCR assay gives a measure of residual disease in patients treated for chronic myeloid leukemia. Recognition that virtually all advanced tumors are associated with both intact circulating tumor cells and products derived from tumors (e.g., cell-free circulating tumor DNA) has led to interest in following tumor burden through sensitive blood tests designed to identify tumor-specific nucleic acid sequences.
Diagnosis of hereditary predisposition to cancer. Germ line mutation of several tumor suppressor genes, such as BRCA1, increases a patient’s risk for developing certain types of cancer. Thus, detection of these mutated alleles may allow the patient and the physician to devise an aggressive screening protocol, as well as an opportunity for prophylactic surgery. In addition, such detection allows genetic counseling of relatives who are at risk.
Therapeutic decision-making. Therapies that directly target specific mutations are increasingly being developed, and thus detection of such mutations in a tumor can guide the development of targeted therapy, as discussed later. It is now becoming evident that certain targetable mutations transgress morphologic categories. One example involves a valine for glutamate substitution in amino acid 600 (V600E) of the serine/threonine kinase BRAF, which you will recall lies downstream of RAS in the growth factor signaling pathway. Melanomas with the V600E BRAF mutation respond well to BRAF inhibitors, whereas melanomas without this mutation show no response. Subsequently, it was realized that the same V600E mutation is also present in a subset of many other diverse cancers, including carcinomas of the colon and thyroid gland, most hairy cell leukemias, and many cases of Langerhans cell histiocytosis (
Fig. 6.36 ). These tumors are morphologically diverse and have distinct cells of origin, but they share identical oncogenic lesions in a common pro-growth pathway.
Molecular Profiling of Tumors:The Future of Cancer Diagnostics
Until recently, molecular studies of tumors involved the analysis of individual genes. However, the past few years have seen the introduction of revolutionary technologies that can rapidly sequence an entire genome; assess http://ebooksmedicine.net
Fig. 6.36 Diversetumortypesthatshareacommonmutation,BRAF(V600E),maybecandidatesfortreatmentwiththesameBRAFinhibitors.
epigenetic modifications genome-wide (the epigenome); quantify all of the RNAs expressed in a cell population (the transcriptome); measure many proteins simultaneously (the proteome); and take a snapshot of all of the cell’s metabolites (the metabolome). Thus, the diagnosis, management and study of cancer has entered the age of “omics!”