Carcinogenesis is rooted in inherited genetic variations and evolves through a series of somatic mutations acquired over time. In a consequence, neoplasm arises as a multi-step process of successive cellular clone selection and expansion leading to progressive cytological and architectural derangement of an affected tissue.

The rate of point mutations within normal cells varies by more than 100-fold within the genome; in tumor cells this variation can be higher and may affect also whole genome regions. While the first cancer “gatekeeping” mutation provides a selective growth advantage of the pre-neoplastic cells to their normal counterparts, subsequent “driver” mutations further confer this advantage. Rates of cancer mutations are variable and range from one base substitution per exome in some pediatric neoplasms to even thousands of mutations per exome in malignancies induced by mutagens, including lung cancers and melanomas. The number of tumor mutations developing in the self-renewing tissues (like in gastrointestinal tract) correlates with age. Point mutations of cancer genes are more frequent than chromosomal rearrangements.

Although cancer originates from a common progenitor, four types of genetic heterogeneity, intratumoral, inter- and intrametastatic, and interpatient, are relevant to carcinogenesis. Therefore, determining somatic mutations is the most common aim of cancer genome-sequencing studies. Current medicine employs elements of molecular diagnostics, usually on the scale of single genes. Next-generation sequencing (NGS) is moving testing from single genes or small panels of genes to large multi-gene disease-targeted panels, expanding clinical applications of molecular profiling. However, the benefit of NGS in cancer studies will be realized when it improves understanding of basic cancer biology. Unfortunately, point mutation frequency can only prioritize genes for further analysis but cannot unambiguously identify “driver” genes.

The question how to analyze genetic variances using NGS is a constant subject of debate. Some authors recommend the focused approach involving the sequencing of specific region of cancer genomes, while others - the whole genome approach, where sequencing of the entire genome is the method of choice. Each approach has its advantages and limitations; of the latter, the cost of sequencing and of storing and analyzing high volumes of data from whole genomes causes that it may not be accessible to most researchers. Based on the background knowledge of the cancer genome, the lecture will present aims of the use of NGS regarding the focused and whole genome sequencing approaches.

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