Biology subjects

Spellman, P. T.

Publications and source records attributed to Spellman, P. T..

3 recordsLinked to original sources

bioRxiv2018

Portraits of genetic intra-tumour heterogeneity and subclonal selection across cancer types

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin and drivers of ITH across cancer types are poorly understood. To address this question, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples, spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions, with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types, and identify cancer type specific subclonal patterns of driver gene mutations, fusions, structural variants and copy-number alterations, as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution, and provide an unprecedented pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

cancer biology↗

bioRxiv2017

The evolutionary history of 2,658 cancers

Cancer develops through a process of somatic evolution. Here, we use whole-genome sequencing of 2,778 tumour samples from 2,658 donors to reconstruct the life history, evolution of mutational processes, and driver mutation sequences of 39 cancer types. The early phases of oncogenesis are driven by point mutations in a small set of driver genes, often including biallelic inactivation of tumour suppressors. Early oncogenesis is also characterised by specific copy number gains, such as trisomy 7 in glioblastoma or isochromosome 17q in medulloblastoma. By contrast, increased genomic instability, a nearly four-fold diversification of driver genes, and an acceleration of point mutation processes are features of later stages. Copy-number alterations often occur in mitotic crises leading to simultaneous gains of multiple chromosomal segments. Timing analysis suggests that driver mutations often precede diagnosis by many years, and in some cases decades, providing a window of opportunity for early cancer detection.

cancer biology↗

bioRxiv2017

Neutral tumor evolution?

Tumor growth is an evolutionary process governed by somatic mutation, clonal selection and random genetic drift, constrained by the co-evolution of the microenvironment1,2. Tumor subclones are subpopulations of tumor cells with a common set of mutations resulting from the expansion of a single cell during tumor development, and have been observed in a significant fraction of cancers and across multiple cancer types3. Peter Nowell proposed that tumors evolve through sequential genetic events4, whereby one cell acquires a selective advantage so that its lineage becomes predominant. According to this traditional model, the selective advantage is conferred by a small set of driver mutations, but, as the subclones that bear them expand successively, they accumulate passenger mutations as well, which can be detected in sequencing experiments1. Genomes of indiv ...

cancer biology↗