Table 1. Lung cancer ctDNA sequencing.
| ID | Histology | Somatic mutation | Variant | Tumour VAF % | ctDNA VAF% | JAX Clinical Knowledgebase (CKB)2 and ClinVar annotation | Implications for Treatment and CKB Reference Link |
|---|---|---|---|---|---|---|---|
| 1178 | Adeno1 | yes | TP53 R273C | 19 | 6.8 | CKB: Hotspot mutation in DNA-binding domain of TP53 (PMID: 22713868); ClinVar: probable pathogenic | Treatment approach: p53 activator, p53 gene therapy (gene-associated clinical trials available) https://ckb.jax.org/geneVariant/show?geneVariantId=3795 |
| no | MET N375S | 37 | 44 | CKB: Lies in extracellular Sema ligand-binding domain, predicted loss of function (PMID: 19723643); ClinVar: benign/ likely benign | May confer resistance to MET targeted agents (PMID: 19723643) https://ckb.jax.org/geneVariant/show?geneVariantId=3356 | ||
| 1530 | Metastatic adeno (brain) | no | MET R988C | 49 | 50 | CKB: Gain of function; no increase in MET phosphorylation, but increased cellular protein phosphorylation and increased proliferation and migration of cultured cells (PMID: 14559814, 20670955, 22973954); ClinVar: conflicting: likely benign(2), uncertain sig(2) | Treatment approach: MET inhibitor (Gene-associated clinical trials available) https://ckb.jax.org/geneVariant/show?geneVariantId=706 |
| yes | MET H1112Y | 26 | 6 | CKB: Gain of function; causes constitutive MET phosphorylation and activation of downstream signaling, and transforming in cell culture (PMID: 15064724, 24061647); not found in ClinVar | Treatment approach: MET inhibitor (Gene-associated clinical trials available) https://ckb.jax.org/geneVariant/show?geneVariantId=1004 | ||
| yes | KRAS G12C | 41 | 8 | CKB: Hotspot mutation, inhibits GTPase activity of KRAS leading to increased activation of downstream signaling pathways promoting tumour formation (PMID: 16051643); ClinVar: pathogenic | Confers resistance to EGFR tyrosine kinase inhibitors; Treatment approach: Pan-MEK inhibitor, Pan-PI3K inhibitor, RAS inhibitor (gene-associated clinical trials ongoing) https://ckb.jax.org/geneVariant/show?geneVariantId=979 | ||
| yes | SMAD4 R361H | 34 | 7 | CKB: Hotspot residue in MH2 domain of SMAD4, with predicted loss of function (PMID: 21763698); ClinVar: pathogenic | Rare in lung cancer and for which there is little evidence for targeted therapies https://ckb.jax.org/geneVariant/show?geneVariantId=1780 | ||
| 1533 | Metastatic adeno | yes | BRAF D594G | 17 | 2 | CKB: Mutation impairs BRAF kinase activity but paradoxically activates MEK and ERK through CRAF transactivation (PMID: 20141835); ClinVar: pathogenic | Results in BRAF inactivation and insensitivity to BRAF inhibitors; Treatment approach: MEK1, MEK2 and pan-MEK inhibitors https://ckb.jax.org/geneVariant/show?geneVariantId=897 |
| yes | KIT G510C | 21 | 2 | Not found in CKB or ClinVar | none | ||
| yes | TP53 G244C | 24 | 3 | Not found in CKB or ClinVar | none | ||
| 594 | Adeno | no | KIT V532I | 50 | 52 | Not found in CKB or ClinVar | none |
| no | MET T1010I | 39 | 48 | CKB: Conflicting reports: increase in MET phosphorylation (PMID: 25605252), or no effect (PMID: 20670955); ClinVar: non-pathogenic | none; https://ckb.jax.org/geneVariant/show?geneVariantId=1388 | ||
| yes | TP53 V172F | 17 | 3 | CKB: Mutation in DNA-binding region of TP53 but uncharacterised so its effect is unknown; not found in ClinVar | none; https://ckb.jax.org/geneVariant/show?geneVariantId=17312 | ||
| 591 | Metastatic adeno | yes | TP53 R249S | 11 | 0.2 | CKB: Hotspot mutation in DNA-binding domain of TP53 (PMID: 22713868), decreased transactivation activity of TP53, and context-dependent transforming ability in cell culture (PMID: 20212049, PMID: 20538734); ClinVar: non-pathogenic | Treatment approach: p53 activator, p53 gene therapy (gene-associated clinical trials available) https://ckb.jax.org/geneVariant/show?geneVariantId=3231 |
| no | JAK3 V722I | 47 | 54 | CKB: Mutation in protein kinase 1 domain of JAK3, confers gain of function and activation of JAK3/STAT3 pathway (PMID: 23689514); ClinVar: no information | Treatment approach: Pan-JAK inhibitor or JAK3 inhibitor https://ckb.jax.org/geneVariant/show?geneVariantId=1066 | ||
| 590 | Adeno | yes | CTNNB1 G34V | 22 | not found | CKB: Mutation within ubiquitination recognition motif of CTNNB1 (PMID: 15064718), gain of function due to nuclear accumulation of CTNNB1 in liver cancer (PMID: 9671767); ClinVar: conflicting: pathogenic(1); uncertain sig(1) | Treatment approach: CTNNB1 inhibitor, PDPK1 inhibitor, Tankyrase inhibitor https://ckb.jax.org/geneVariant/show?geneVariantId=3973 |
| 572 | Adeno | negative | |||||
| 463 | Small cell lung cancer | yes | TP53 G245D | not avail. | 4 | CKB: Hotspot mutation in DNA-binding domain of TP53 (PMID: 22713868), decreased activation of p21, and also confers a gain-of-function (PMID: 22214764); ClinVar: pathogenic | Treatment approach: p53 activator, p53 gene therapy (gene-associated clinical trials available) https://ckb.jax.org/geneVariant/show?geneVariantId=4658 |
| no | TP53 M237I | 9 | CKB: Mutation in DNA-binding domain of TP53 (PMID: 22713868), decreased TP53 transactivation activity in cell culture (PMID: 16492679); ClinVar: pathogenic/likely pathogenic | https://ckb.jax.org/geneVariant/show?geneVariantId=16637 | |||
| 593 | Squamous cell | yes | CDKN2A C72S | not avail. | 17 | Not found in CKB or ClinVar | none |
| yes | PTEN S59* | 21 | CKB: Results in premature truncation of PTEN protein, predicted loss of function (UniProt.org); not found in ClinVar | Treatment approach: Pan-AKT inhibitor, AKT1 inhibitor, AKT2 inhibitor, AKT3 inhibitor, Pan-PI3K inhibitor (gene-associated clinical trials available) https://ckb.jax.org/geneVariant/show?geneVariantId=4433 | |||
| yes | TP53 M237I | 28 | CKB: Mutation in DNA-binding domain of TP53 (PMID: 22713868), decreased TP53 transactivation activity in cell culture (PMID: 16492679); ClinVar: pathogenic/likely pathogenic | https://ckb.jax.org/geneVariant/show?geneVariantId=16637 | |||
| no | TP53 R175H | 2 | CKB: Hotspot mutation in DNA-binding domain of TP53 (PMID: 22713868), decreased activation of TP53 targets, also confers gain of function to TP53, with aberrant activation of gene transcription (PMID: 10713666, 22114072); ClinVar: pathogenic | Treatment approach: p53 activator, p53 gene therapy (gene-associated clinical trials available) https://ckb.jax.org/geneVariant/show?geneVariantId=735 | |||
| 466 | Squamous cell | yes | TP53 R282W | not avail. | 2 | CKB: Hotspot mutation in DNA-binding domain of TP53 (PMID: 22713868), decreased activation of TP53 targets, inhibited AMPK signaling, and promoted tumour development in mouse models (PMID: 24857548); ClinVar: conflicting: likely benign(2); pathogenic(2) | Treatment approach: p53 activator, p53 gene therapy (gene-associated clinical trials available) https://ckb.jax.org/geneVariant/show?geneVariantId=4744 |
| 538 | Squamous cell | yes | TP53 Y220C | not avail. | 0.6 | CKB: Hotspot mutation in DNA-binding domain of TP53 (PMID: 17401432), loss of function, decreased TP53 transcriptional activity in cell culture (PMID: 16861262, 23630318); ClinVar: pathogenic | Treatment approach: p53 activator, p53 gene therapy (gene-associated clinical trials available) https://ckb.jax.org/geneVariant/show?geneVariantId=980 |
| 462 | Carcinoid tumour | negative | not avail. | negative |
Blood samples were drawn from patients prior to bronchoscopy. Plasma DNA and genomic DNA from each patient were sequenced using Ampliseq Cancer Hotspot Panel v2, using one plasma DNA:gDNA paired sample per 318 chip. Tumour DNA was sequenced when enough bronchoscopy material was available.
1Adeno, adenocarcinoma.
2CKB website content is for educational and research purposes only.