Interpreting infrequent somatic variants remains a challenge in cancer genomics. We developed CRISPR-VUS, a framework using public Cancer Dependency Map data to identify Dependency-Associated Mutations (DAMs) - variants linked to increased host-gene dependency - with resolution extending to singleton events. Analysis of 977 cell lines across 36 cancer-types identified 2,376 DAMs in 1,383 genes, including 1,260 not established as cancer drivers. DAM-bearing genes converge on oncogenic networks, while recurrence in matched tumours, functional-impact predictions, tractability and pharmacological associations enable prioritisation. Prime editing showed that the prioritised NSCLC-specific RTN4IP1 p.A80T DAM conferred a significant competitive growth advantage in a lung epithelial model, nominating a candidate driver allele. Exploratory pharmacological testing showed a greater maximal istaroxime response in ATP1B3 p.I189M-bearing RKO cells than in ATP1B3-wild-type HCT15 cells. CRISPR-VUS combines discovery with evidence-guided prioritisation to nominate candidate drivers, therapeutic targets and drug-repositioning hypotheses. Interactive results are available at https://vus-portal.fht.org/.
Interpreting infrequent somatic variants remains a challenge in cancer genomics. We developed CRISPR-VUS, a framework using public Cancer Dependency Map data to identify Dependency-Associated Mutations (DAMs) - variants linked to increased host-gene dependency - with resolution extending to singleton events. Analysis of 977 cell lines across 36 cancer-types identified 2,376 DAMs in 1,383 genes, including 1,260 not established as cancer drivers. DAM-bearing genes converge on oncogenic networks, while recurrence in matched tumours, functional-impact predictions, tractability and pharmacological associations enable prioritisation. Prime editing showed that the prioritised NSCLC-specific RTN4IP1 p.A80T DAM conferred a significant competitive growth advantage in a lung epithelial model, nominating a candidate driver allele. Exploratory pharmacological testing showed a greater maximal istaroxime response in ATP1B3 p.I189M-bearing RKO cells than in ATP1B3-wild-type HCT15 cells. CRISPR-VUS combines discovery with evidence-guided prioritisation to nominate candidate drivers, therapeutic targets and drug-repositioning hypotheses. Interactive results are available at https://vus-portal.fht.org/.
The functional interpretation of infrequent somatic variants remains a challenge in cancer genomics. We developed CRISPR-VUS, a computational framework using public Cancer Dependency Map data to identify Dependency-Associated Mutations (DAMs) - somatic variants associated with increased dependency on their host genes - with resolution extending to singleton events. Across 977 cell lines and 36 cancer types, CRISPR-VUS identified 2,376 DAMs in 1,383 genes, including 1,260 genes not established as cancer drivers. These genes converge on canonical oncogenic networks, while occurrence in histology-matched patient tumours, functional-impact predictions, target tractability and pharmacological associations enable prioritisation. Prospective validation of prioritised DAMs showed that prime-edited RTN4IP1 p.A80T conferred a significant competitive growth advantage in a lineage-relevant lung epithelial model, nominating a candidate NSCLC oncogenic driver allele. Pharmacological testing also showed significantly greater istaroxime sensitivity in ATP1B3 p.I189M-bearing colorectal cancer cells. CRISPR-VUS expands rare-variant interpretation and nominates testable dependencies, therapeutic targets and drug-repositioning opportunities. Results are available at https://vus-portal.fht.org/.
The functional interpretation of infrequent somatic variants remains a challenge in cancer genomics. We developed CRISPR-VUS, a computational framework using public Cancer Dependency Map data to identify Dependency-Associated Mutations (DAMs) - somatic variants associated with increased dependency on their host genes - with resolution extending to singleton events. Across 977 cell lines and 36 cancer types, CRISPR-VUS identified 2,376 DAMs in 1,383 genes, including 1,260 genes not established as cancer drivers. These genes converge on canonical oncogenic networks, while occurrence in histology-matched patient tumours, functional-impact predictions, target tractability and pharmacological associations enable prioritisation. Prospective validation of prioritised DAMs showed that prime-edited RTN4IP1 p.A80T conferred a significant competitive growth advantage in a lineage-relevant lung epithelial model, nominating a candidate NSCLC oncogenic driver allele. Pharmacological testing also showed significantly greater istaroxime sensitivity in ATP1B3 p.I189M-bearing colorectal cancer cells. CRISPR-VUS expands rare-variant interpretation and nominates testable dependencies, therapeutic targets and drug-repositioning opportunities. Results are available at https://vus-portal.fht.org/.
Francesco Iorio· Figshare· 0 citations
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