Somatic mutation variant analysis in rural, resectable non‐small cell lung carcinoma patients

Mitchem, Jonathan B.; Miller, Amanda; Manjunath, Yariswamy; Barbirou, Mouadh; Raju, Murugesan; Shen, Yuanyuan; Li, Guangfu; Avella, Diego M.; Chaudhuri, Aadel A.; Shyu, Chi‐Ren; Warren, Wesley C.; Tonellato, Peter J.; Kaifi, Jussuf T.

doi:10.1016/j.cancergen.2022.09.008

Cited by 2 publications

(1 citation statement)

References 26 publications

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“…Whole exome sequencing confirmed that somatic mutations vastly matched between primary tumors and PDTOs, and only one out of six PDTOs showed a difference in a driver mutation (KRAS) in comparison to the primary tumor. Also, identified somatic mutations matched the ones commonly found in rural Midwest American cohorts consisting of heavy smokers (which is the same population we enrolled from for the present study) (49). Organoid platforms have also been utilized to understand the changes in transcriptional programs at various stages of tumorigenesis (50).…”

Section: Discussionmentioning

confidence: 67%

Patient-derived tumor organoids from resected non-small cell lung cancers for high-throughput response testing with approved and repurposed drugs

Suvilesh,

Manjunath,

Nussbaum

et al. 2023

Preprint

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Background: The five-year survival for non-metastatic non-small cell lung cancer (NSCLC) patients undergoing curative surgery remains poor at ~50% that is due to locoregional and/or distant metastatic recurrences. Patient-derived tumor organoids (PDTOs) have high potential as clinically relevant high-throughput drug testing platforms to personalize and improve treatment of NSCLC patients. We aimed to develop PDTOs from non-metastatic NSCLC patients to assess their suitability to study tumor heterogeneities and personalized drug responses. Methods: Ten non-metastatic (stage I-IIIA) NSCLC patients undergoing curative surgical resection were prospectively enrolled. PDTOs were established from resected lung tumor tissues and were compared with matched primary tumors by histopathology, immunohistochemistry, whole exome and whole transcriptome sequencing analysis. PDTO responses to standard of care carboplatin/paclitaxel chemotherapy were determined by measuring organoid growth using bright-field 3D imaging. Transcriptomic differential gene expression analysis identified molecular targets for drug repurposing to overcome chemoresistance. Results: NSCLC PDTOs were successfully generated from all 10 (100%) primary tumors with a median time of 12 days (range 4-16 days). All 10 PDTOs could be grown from cryopreserved tumor tissues or reconstituted from frozen PDTOs (living biobank). PDTOs retained histopathological, immunohistochemical protein expression and mutational landscape of the matched primary tumors. Microenvironment cell population analysis revealed epithelial cell signatures of the PDTOs that matched the patients lung tumor tissues. Treatment responses of PDTOs to carboplatin/paclitaxel were determined by growth differences versus vehicle control group. 5/10 (50%) PDTOs were chemo-sensitive, whereas 5/10 (50%) were chemo-resistant. Upregulation of aldo-keto reductases (AKR1B10/15) was observed in chemoresistant PDTOs by differential gene expression analysis and confirmed by real-time PCR and immunohistochemistry in PDTOs and tumor tissues. Epalrestat, an anti-diabetic AKR1B10 inhibitory drug, was repurposed to effectively sensitize PDTOs to carboplatin/paclitaxel. Conclusions: PDTOs can be established from resected NSCLC primary tumor tissues with high success rates and conserve cellular, molecular and genomic characteristics of the matched NSCLC tumors. PDTOs can serve as clinically applicable and relevant personalized drug screening platforms to evaluate the therapeutic efficacy of drugs, including repurposed drugs, to overcome chemoresistance.

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Section: Discussionmentioning

confidence: 67%

Patient-derived tumor organoids from resected non-small cell lung cancers for high-throughput response testing with approved and repurposed drugs

Suvilesh,

Manjunath,

Nussbaum

et al. 2023

Preprint

Self Cite

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Identification of molecular biomarkers associated with non-small-cell lung carcinoma (NSCLC) using whole-exome sequencing

Singh,

Katiyar,

Malik

et al. 2023

CBM

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OBJECTIVES: Significant progress has been made in the treatment of patients with pulmonary adenocarcinoma (ADCA) based on molecular profiling. However, no such molecular target exists for squamous cell carcinoma (SQCC). An exome sequence may provide new markers for personalized medicine for lung cancer patients of all subtypes. The current study aims to discover new genetic markers that can be used as universal biomarkers for non-small cell lung cancer (NSCLC). METHODS: WES of 19 advanced NSCLC patients (10 ADCA and 9 SQCC) was performed using Illumina HiSeq 2000. Variant calling was performed using GATK HaplotypeCaller and then the impacts of variants on protein structure or function were predicted using SnpEff and ANNOVAR. The clinical impact of somatic variants in cancer was assessed using cancer archives. Somatic variants were further prioritized using a knowledge-driven variant interpretation approach. Sanger sequencing was used to validate functionally important variants. RESULTS: We identified 24 rare single-nucleotide variants (SNVs) including 17 non-synonymous SNVs, and 7 INDELs in 18 genes possibly linked to lung carcinoma. Variants were classified as known somatic (n= 10), deleterious (n= 8), and variant of uncertain significance (n= 6). We found TBP and MPRIP genes exclusively associated with ADCA subtypes, FBOX6 with SQCC subtypes and GPRIN2, KCNJ18 and TEKT4 genes mutated in all the patients. The Sanger sequencing of 10 high-confidence somatic SNVs showed 100% concordance in 7 genes, and 80% concordance in the remaining 3 genes. CONCLUSIONS: Our bioinformatics analysis identified KCNJ18, GPRIN2, TEKT4, HRNR, FOLR3, ESSRA, CTBP2, MPRIP, TBP, and FBXO6 may contribute to progression in NSCLC and could be used as new biomarkers for the treatment. The mechanism by which GPRIN2, KCNJ12, and TEKT4 contribute to tumorigenesis is unclear, but our results suggest they may play an important role in NSCLC and it is worth investigating in future.

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Somatic mutation variant analysis in rural, resectable non‐small cell lung carcinoma patients

Cited by 2 publications

References 26 publications

Patient-derived tumor organoids from resected non-small cell lung cancers for high-throughput response testing with approved and repurposed drugs

Patient-derived tumor organoids from resected non-small cell lung cancers for high-throughput response testing with approved and repurposed drugs

Identification of molecular biomarkers associated with non-small-cell lung carcinoma (NSCLC) using whole-exome sequencing

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