Current and future molecular profiling of cancer by next-generation sequencing

Abstract

Advances in the new sequencing technologies have enabled us to explore global genetic alterations including driver genes in a wide range of cancers. Concordantly, successes of molecular target therapy promoted the validity of tumor classification based on the combination of targetable genetic abnormalities, and next-generation sequencing-based genetic profiling using target gene capturing or multiplex-polymerase chain reaction has already been tested or adapted in many cancer centers. Driver gene-based classification may be applicable beyond organs, and clinical trials incorporating this genomic information, called as a basket trial, have been executed, although it should be considered that similar therapeutic efficacies against driver mutations are not invariably maintained among different cancer types. Research efforts to identify still missing driver genes in rare cancers, to complete functional annotation of infrequent driver genes, and multiple-layered omics approaches are further expected for better classification of tumor. Emerging clinical interests in the development of immunotherapies postulate a new molecular classification of tumors. Recent studies reported that total number of mutations and the frequent appearance of neo-antigens by protein-coding mutations were associated with a better response, and genetic evaluation of both tumor and host immune system by sequencing is expected to contribute to the personalized immunotherapies in the near future. Lastly intratumoral molecular heterogeneity challenges the current 'static' molecular classification of tumor. For example, dynamic change in clonal constitution within tumor plays an important role in acquired drug resistance. It has been extensively explored whether liquid biopsy-based molecular profiling can resolve currently confronting difficulties.