A practical guide for mutational signature analysis in hematological malignancies Journal Article
| Authors: | Maura, F.; Degasperi, A.; Nadeu, F.; Leongamornlert, D.; Davies, H.; Moore, L.; Royo, R.; Ziccheddu, B.; Puente, X. S.; Avet-Loiseau, H.; Campbell, P. J.; Nik-Zainal, S.; Campo, E.; Munshi, N.; Bolli, N. |
| Article Title: | A practical guide for mutational signature analysis in hematological malignancies |
| Abstract: | Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data. © 2019, The Author(s). |
| Keywords: | gene mutation; major clinical study; single nucleotide polymorphism; gene deletion; mutation; pathogenesis; homologous recombination; multiple myeloma; breast cancer; cohort analysis; genetic variation; practice guideline; mutational analysis; brca1 protein; brca2 protein; hematologic malignancy; somatic hypermutation; activation induced cytidine deaminase; immunoglobulin heavy chain; gene rearrangement; immunoglobulin variable region; algorithm; genomic instability; genomics; genome; pathogenicity; gene insertion; chronic lymphatic leukemia; immunoglobulin kappa chain; bioinformatics; disability; hematology; copy number variation; b lymphocyte receptor; acute myeloid leukemia; next generation sequencing; performance assessment; recombination repair; cancer; human; article; whole genome sequencing; apolipoprotein b mrna editing enzyme catalytic polypeptide like |
| Journal Title: | Nature Communications |
| Volume: | 10 |
| Issue: | 1 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2019-07-05 |
| Start Page: | 2969 |
| Language: | English |
| DOI: | 10.1038/s41467-019-11037-8 |
| PUBMED: | 31278357 |
| PROVIDER: | scopus |
| PMCID: | PMC6611883 |
| DOI/URL: | |
| Notes: | Article -- Correction issued, see DOI 10.1038/s41467-019-11468-3 -- Export Date: 3 October 2019 -- Source: Scopus |
