Interpretation of Missense Variants Found in Association with Cancer

Abstract

Abstract Dynamic changes in the genome characterise the onset, progression, diffusion and metastasis of cancer. Genomic changes may confer a growth advantage: gain of function mutations in oncogenes and loss of function in tumour suppressor may drive the tumour invasion and the loss of control mechanism in the hosts. Genome instability and inflammation are at the basis of the genetic changes reported in the Cancer Genome Atlas during these last 20 years. Cancer genome landscape has been extensively analysed with the aim to distinguish, in the tumour samples, the cancer‐related mutations from those neutral or benign. Studies in cancer tissues indicate that the somatic mutations observed effect from 33 to 66 genes and that 95% of these mutations are single‐nucleotide variants, mainly missense, or nonsynonymous variants, that is a single nucleotide substitution leads to a change in the protein sequence. The vast amount of data collected is not accompanied yet by a meaningful interpretation, and a linear connection between clinics and biological data is not even on the way. We report on case studies of missense mutations in frequently mutated cancer genes, in relation to the effect of missense mutations on the protein structure, functions and stability. Key Concepts Cancer is a complex disease characterised by dynamic changes in the genome. Germline and somatic protein variants are present in cancer. Missense mutations in oncogenes or in tumour suppressor genes may promote uncontrolled cellular growth. Missense mutations may affect protein structure, stability and function. Structural and functional analysis of protein missense mutations in cancer may help in the development of personalised drugs.