Pan-cancer association of DNA repair deficiencies with whole-genome mutational patterns
- Aarhus University Hospital, Denmark
- University of Copenhagen, Denmark
Abstract
DNA repair deficiencies in cancers may result in characteristic mutational patterns, as exemplified by deficiency of BRCA1/2 and efficacy prediction for PARP-inhibitors. We trained and evaluated predictive models for loss-of-function (LOF) of 145 individual DDR genes based on genome-wide mutational patterns, including structural variants, indels, and base-substitution signatures. We identified 24 genes whose deficiency could be predicted with good accuracy, including expected mutational patterns for BRCA1/2, MSH3/6, TP53, and CDK12 LOF variants. CDK12 is associated with tandem-duplications, and we here demonstrate that this association can accurately predict gene deficiency in prostate cancers (area under the ROC curve=0.97). Our novel associations include mono- or biallelic LOF variants of ATRX, IDH1, HERC2, CDKN2A, PTEN, and SMARCA4, and our systematic approach yielded a catalogue of predictive models, which may provide targets for further research and development of treatment, and potentially help guide therapy.
Data availability
This study is based on analyses of human germline and cancer somatic variant data. The data sets were generated and made available by the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium and from the Hartwig Medical Foundation (HMF). The majority of the data cannot be publicly accessed as it includes protected personal data, including germline variants, which cannot be made publicly available. However, accession to the underlying data sets can be achieved through applications to ICGC/TCGA and HMF as described below.The public parts of the PCAWG data set are available at https://dcc.icgc.org/releases/PCAWG, whereas controlled files may be accessed through applications to gbGaP and DACO, which should include a project proposal, as instructed on this site https://docs.icgc.org/pcawg/data/. The ICGC study ID of the project is EGAS00001001692.The HMF data used in this project may be found by accession code DR-044 and can be obtained by submitting an application with a project proposal to the Hartwig Medical Foundation (https://www.hartwigmedicalfoundation.nl/en).Non-personal summary data have been supplied in supplementary tables S1 to S9:Supplementary Table 1: All included tumours and their primary tumour locationsSupplementary Table 2: 736 DDR genes, hg19 coordinates and the number ofpathogenic events across 6,065 cancer genomesSupplementary Table 3: All SBS signature contributions, indels counts, and1104 SV counts, per sample; zip-compressed; tab-separated values (.tsv), may be opened in Microsoft ExcelSupplementary Table 4: All SBS signature contributions, indels counts, andSV counts, per sample, log-transformed and scaled to z-scores; zip-compressed; tab-separated values (.tsv), may be opened in Microsoft ExcelSupplementary Table 5: Proposed Etiologies of base substitution signaturesSupplementary Table 6: All models (n=535)Supplementary Table 7: Pathogenic events in each of the 535 LOF-setsSupplementary Table 8: Shortlisted models (n=48)Supplementary Table 9: Correlation between features in shortlisted modelsSupplementary Table 10: Survival analysis for the shortlisted modelsThe third-party software used for data analysis includes:Pathogenicity annotation using CADD annotation software, which may be accessed at https://cadd.gs.washington.eduSignature analysis using Signature Tools Lib, which has been installed from the GitHub: https://github.com/Nik-Zainal-Group/signature.tools.libCode that we developed locally for the analysis can be accessed at:https://github.com/SimonGrund/DDR_Predict
Article and author information
Author details
Jakob Skou Pedersen
Funding
Novo Nordisk Fonden (NNF15OC0016662)
- Eva R Hoffmann
Cancer Research UK (C23210/A7574)
- Eva R Hoffmann
Danmarks Frie Forskningsfond (8021-00419B)
- Jakob Skou Pedersen
Kræftens Bekæmpelse (R307-A17932)
- Jakob Skou Pedersen
Aarhus Universitets Forskningsfond (AUFF-E-2020-6-14)
- Jakob Skou Pedersen
Sundhedsvidenskabelige Fakultet, Aarhus Universitet (PhD stipend)
- Simon Grund Sørensen
Sundhed, Region Midtjylland (A2972)
- Gustav Alexander Poulsgaard
Danmarks Grundforskningsfond (DNRF115)
- Eva R Hoffmann
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: We analysed data generated and made available by the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) as well as the Hartwig Medical Foundation (HMF). The research conforms to the principles of the Helsinki Declaration.
Copyright
© 2023, Sørensen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,667
- views
-
- 321
- downloads
-
- 3
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Pan-cancer association of DNA repair deficiencies with whole-genome mutational patterns
eLife 12:e81224.
https://doi.org/10.7554/eLife.81224
Further reading
-
- Cancer Biology
- Immunology and Inflammation
The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or may develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are believed to be significantly influenced by the tumor microenvironment through secretory factors and biased cell-cell interactions. To explore the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers. We demonstrated that draining LNs are differentially involved in the interaction with the tumor site, and that significant heterogeneity exists even between different parts of a single lymph node (LN). Next, we confirmed and elaborated upon previous observations regarding intratumoral immunoglobulin heterogeneity. We identified B cell receptor (BCR) clonotypes that were expanded in tumors relative to draining LNs and blood and observed that these tumor-expanded clonotypes were less hypermutated than non-expanded (ubiquitous) clonotypes. Furthermore, we observed a shift in the properties of complementarity-determining region 3 of the BCR heavy chain (CDR-H3) towards less mature and less specific BCR repertoire in tumor-infiltrating B-cells compared to circulating B-cells, which may indicate less stringent control for antibody-producing B cell development in tumor microenvironment (TME). In addition, we found repertoire-level evidence that B-cells may be selected according to their CDR-H3 physicochemical properties before they activate somatic hypermutation (SHM). Altogether, our work outlines a broad picture of the differences in the tumor BCR repertoire relative to non-tumor tissues and points to the unexpected features of the SHM process.
-
- Cancer Biology
- Computational and Systems Biology
Effects from aging in single cells are heterogenous, whereas at the organ- and tissue-levels aging phenotypes tend to appear as stereotypical changes. The mammary epithelium is a bilayer of two major phenotypically and functionally distinct cell lineages: luminal epithelial and myoepithelial cells. Mammary luminal epithelia exhibit substantial stereotypical changes with age that merit attention because these cells are the putative cells-of-origin for breast cancers. We hypothesize that effects from aging that impinge upon maintenance of lineage fidelity increase susceptibility to cancer initiation. We generated and analyzed transcriptomes from primary luminal epithelial and myoepithelial cells from younger <30 (y)ears old and older >55 y women. In addition to age-dependent directional changes in gene expression, we observed increased transcriptional variance with age that contributed to genome-wide loss of lineage fidelity. Age-dependent variant responses were common to both lineages, whereas directional changes were almost exclusively detected in luminal epithelia and involved altered regulation of chromatin and genome organizers such as SATB1. Epithelial expression variance of gap junction protein GJB6 increased with age, and modulation of GJB6 expression in heterochronous co-cultures revealed that it provided a communication conduit from myoepithelial cells that drove directional change in luminal cells. Age-dependent luminal transcriptomes comprised a prominent signal that could be detected in bulk tissue during aging and transition into cancers. A machine learning classifier based on luminal-specific aging distinguished normal from cancer tissue and was highly predictive of breast cancer subtype. We speculate that luminal epithelia are the ultimate site of integration of the variant responses to aging in their surrounding tissue, and that their emergent phenotype both endows cells with the ability to become cancer-cells-of-origin and represents a biosensor that presages cancer susceptibility.
