Gain-of-Function Mutations: An Emerging Advantage for Cancer Biology

GOF mutations are an important type of mutation that occur in various types of cancer but have garnered little attention. GOF mutations play crucial roles in the development and progression of various types of cancer. Systematic analysis of the interaction and regulator networks perturbed by GOF mutations can effectively reveal the functional consequences. The combination of computational and experimental approaches is instrumental in identifying driver GOF mutations as well as identifying potential therapeutic targets. Advances in next-generation sequencing have identified thousands of genomic variants that perturb the normal functions of proteins, further contributing to diverse phenotypic consequences in cancer. Elucidating the functional pathways altered by loss-of-function (LOF) or gain-of-function (GOF) mutations will be crucial for prioritizing cancer-causing variants and their resultant therapeutic liabilities. In this review, we highlight the fundamental function of GOF mutations and discuss the potential mechanistic effects in the context of signaling networks. We also summarize advances in experimental and computational resources, which will dramatically help with studies on the functional and phenotypic consequences of mutations. Together, systematic investigations of the function of GOF mutations will provide an important missing piece for cancer biology and precision therapy. Advances in next-generation sequencing have identified thousands of genomic variants that perturb the normal functions of proteins, further contributing to diverse phenotypic consequences in cancer. Elucidating the functional pathways altered by loss-of-function (LOF) or gain-of-function (GOF) mutations will be crucial for prioritizing cancer-causing variants and their resultant therapeutic liabilities. In this review, we highlight the fundamental function of GOF mutations and discuss the potential mechanistic effects in the context of signaling networks. We also summarize advances in experimental and computational resources, which will dramatically help with studies on the functional and phenotypic consequences of mutations. Together, systematic investigations of the function of GOF mutations will provide an important missing piece for cancer biology and precision therapy. method used to identify protein–DNA interactions, which combines chromatin immunoprecipitation with DNA sequencing to identify the binding sites of DNA-associated proteins. observed in the same protein complex, which are a form of quaternary structure. variants found in the human population; not necessarily disease causing. mutations that are causally implicated in oncogenesis. type of genetic variant in which altered genes or noncoding RNAs possess a new molecular function or a new pattern of expression. differences between the DNA sequence of an individual when compared with the DNA sequence of a reference genome. entire set of molecular interactions in a particular cell. protein regions that lack a stable tertiary structure. genetic variants that are predicted to disrupt the function of coding genes and noncoding RNAs. small noncoding RNA of approximately 22 nucleotides that functions in post-transcriptional regulation of gene expression via base pairing. point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. mutations that do not confer a clonal growth advantage and do not contribute to cancer development. a commonly used representation of motifs in biological sequences. conserved part of a given protein sequence and tertiary structure that can evolve, function, and exist independently of the rest of the protein chain. proteins that contain various structural motifs to bind double- or single-stranded RNAs. self-sufficient functional sequences that specify interaction sites for other molecules and thus mediate a multitude of functions. regions of the genome composed of multiple enhancers that are collectively bound by other proteins and drive transcription of genes. proteins that control the rate of transcription of genetic information from DNA to mRNA, by binding to a specific DNA sequence and can interact with number of other proteins.