Prostate cancer (PCa) is the most common noncutaneous malignancy affecting American men and the second most common cause of cancer death. The traditional risk classification schemes for PCa are limited due to the vast clinical and molecular heterogeneity of the disease. Fortunately, recent advancements in sequencing technologies have provided us with valuable insight into the genomics of PCa. To date, a wide array of recurrent genomic alterations in PCa have been identified. Incorporating these distinct molecular subtypes of PCa into prediction models provides opportunities for improved risk stratification and ultimately better patient outcomes. In this review, we summarize the key molecular subtypes of PCa and focus on those genomic alterations that have clinical implications for diagnosis, prognosis, and therapeutic response.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer. This review gives an overview of the current knowledge of molecular mechanisms of colorectal carcinogenesis and the role of molecular testing in the management of CRC. The majority of CRCs arise from precursor lesions such as adenoma, transforming to adenocarcinoma. Three molecular carcinogenesis pathways have been identified; (1) chromosomal instability, (2) microsatellite instability (MSI), and (3) CpG island methylator phenotype, each account for ~85%, 15%, and 17%, respectively. Evaluation of MSI status, extended RAS mutation analysis, and BRAF mutation analysis are recommended by the guideline published by joint effort from professional societies. MSI testing is important for identification of Lynch syndrome patients and prognostic and predictive markers. Extended RAS testing is an important predictive marker for antiepidermal growth factor receptor therapy. BRAF p.V600 mutation status can be used as prognostic marker, but not predictive marker for antiepidermal growth factor receptor therapies. Emerging technologies utilizing high throughput sequencing have introduced novel biomarkers and testing strategies. Tumor mutation burden predicts immunotherapy response in addition to MSI status. Liquid biopsy can be utilized when adequate tissue sample is not available or for monitoring therapy response. However, assay standardization and guidelines and recommendations for utilization of these assay will be needed. The advancement in CRC research and technologies will allow better prognostication and therapy stratification for the management of patients with CRCs.
Urothelial carcinoma (UC) is the most common malignant neoplasm of the bladder that encompasses a wide spectrum of histopathologic features and various molecular alterations and subtypes, responsible for its significant morphologic and genomic heterogeneity. Morphologically, in addition to classic UC (not otherwise specified), many well documented variant histologies are a common finding in invasive UC, and include squamous, glandular, micropapillary, sarcomatoid, small cell/neuroendocrine, clear cell, lymphoepithelioma-like, and plasmacytoid types, among others. This review provides an update on the recent advances in the molecular characterization and novel molecular taxonomy of UC and variant histologies.
Non–small cell lung cancer (NSCLC), since the recognition of epidermal growth factor receptor (EGFR) mutations that sensitized tumors to EGFR tyrosine kinase inhibitors, has been a poster child for precision oncology in solid tumors. The emergence of resistance to the EGFR tyrosine kinase inhibitors led to the unveiling of multiple resistance mechanisms that are now recognized to be frequent mechanisms across multiple tumor types. Coevolution of technological advancements in testing methods available to clinical laboratories now has identified a growing number of molecularly defined subsets of NSCLC that have new therapeutic implications. In addition, identifying patients eligible for immunotherapy is another goal for precision oncology. Recently, studies suggest that TMB may be a promising biomarker for selecting patients with NSCLC for immunotherapy. This review focuses on emerging potentially targetable alterations specifically in RET, ERBB2 (HER2), MET, and KRAS and current evidence and controversies surrounding TMB testing.
Cancer classification aims to provide an accurate diagnosis of the disease and prediction of tumor behavior to facilitate oncologic decision making. Traditional breast cancer classification, mainly based on clinicopathologic features and assessment of routine biomarkers, may not capture the varied clinical courses of individual breast cancers. The underlying biology in cancer development and progression is complicated. Recent findings from high-throughput technologies added important information with regard to the underlying genetic alterations and the biological events in breast cancer. The information provides insights into new treatment strategies and patient stratifications that impact on the management of breast cancer patients. This review provides an overview of recent data on high throughput analysis of breast cancers, and it analyzes the relationship of these findings with traditional breast cancer classification and their clinical potentials.
Molecular studies have identified distinct genomic drivers providing insights in biology of brain tumors. Advances in genetic and epigenetic analysis, as well as development of mutation-specific antibodies enable more accurate classification of histologically indistinguishable tumors. Compared with histopathologic grading, molecular biomarkers are also superior in predicting natural behavior of tumors and therapeutic response. Diffuse gliomas can be separated in astrocytoma and oligodendroglioma based on IDH1/2, ATRX, and TP53 mutational status. Pediatric gliomas are molecularly distinct from adult tumors and molecular drivers include histone H3 genes and fusions involving the MAPK pathway. Using genetic and epigenetic profiling, ependymal tumors, medulloblastomas, and atypical teratoid/rhabdoid tumors can be separated in biologically and clinically distinct entities. Identification of novel gene fusions and matched DNA methylation signatures enable accurate diagnosis of primitive neuroectodermal tumors, which were previously misdiagnosed. Genomic classification of central nervous system tumors is being readily translated into the clinical practice and will enable molecularly based patient management and clinical trials.