Journal article
Quantification of within-sample genetic heterogeneity from SNP-array data
University of Lyon1
Queen Mary University of London2
Department of Systems Biology, Technical University of Denmark3
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark4
National Veterinary Institute, Technical University of Denmark5
T-cells & Cancer, Division of Immunology & Vaccinology, National Veterinary Institute, Technical University of Denmark6
Department of Bio and Health Informatics, Technical University of Denmark7
Cancer Genomics, Department of Bio and Health Informatics, Technical University of Denmark8
Intra-tumour genetic heterogeneity (ITH) fosters drug resistance and is a critical hurdle to clinical treatment. ITH can be well-measured using multi-region sampling but this is costly and challenging to implement. There is therefore a need for tools to estimate ITH in individual samples, using standard genomic data such as SNP-arrays, that could be implemented routinely.
We designed two novel scores S and R, respectively based on the Shannon diversity index and Ripley's L statistic of spatial homogeneity, to quantify ITH in single SNP-array samples. We created in-silico and in-vitro mixtures of tumour clones, in which diversity was known for benchmarking purposes. We found significant but highly-variable associations of our scores with diversity in-silico (p <0.001) and moderate associations in-vitro (p = 0.015 and p = 0.085).
Our scores were also correlated to previous ITH estimates from sequencing data but heterogeneity in the fraction of tumour cells present across samples hampered accurate quantification. The prognostic potential of both scores was moderate but significantly predictive of survival in several tumour types (corrected p = 0.03).
Our work thus shows how individual SNP-arrays reveal intra-sample clonal diversity with moderate accuracy.
Language: | English |
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Publisher: | Nature Publishing Group UK |
Year: | 2017 |
Pages: | 3248 |
ISSN: | 20452322 |
Types: | Journal article |
DOI: | 10.1038/s41598-017-03496-0 |
ORCIDs: | 0000-0003-2928-6017 and 0000-0001-9582-1597 |