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Jun Liu
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-116 - The Potential of Assessing Blood Tumor Mutation Burden (bTMB) Using a Large Panel (ID 13224)
16:45 - 18:00 | Author(s): Jun Liu
- Abstract
Background
TMB, measuring the number of non-synonymous mutation per megabase of DNA, has shown to associate with response to checkpoint inhibitors in a number of cancers, including lung cancer. Whole exome sequencing (WES), the gold standard for evaluating TMB, is less cost-effective. Multiple studies have shown large panels can yield comparable results in tissue samples. However, the feasibility of assessing bTMB using a large panel has not been extensively evaluated. In this study, we evaluated TMB of 30 treatment-naïve advanced NSCLC patients by performing WES on tissue samples as well as targeted sequencing on matched tissue and plasma samples.
a9ded1e5ce5d75814730bb4caaf49419 Method
WES was performed on tissue samples with an average sequencing depth of 300x. Targeted sequencing was performed on matched tissue and plasma using a panel consisting of 520 cancer-related genes, spanning 1.6Mb of human genome. An average sequencing depth of 1,000X and 10,000x were achieved for tissue and plasma samples, respectively. TMB was calculated as the ratio of mutation count to the size of coding region of the panel (1.26Mb), excluding copy number variations, fusions, large genomic rearrangements and mutations occurring on the kinase domain of EGFR and ALK.
4c3880bb027f159e801041b1021e88e8 Result
In tissue samples, TMB derived from WES and our panel is comparable with a R2 value of 0.87, and a correlation value of 0.86. cfDNA from 8 patients had no mutation detected using the 520 panel potentially due to low fraction of ctDNA present in the circulation. TMB derived from cfDNA of the remaining 22 patients showed a good correlation with TMB derived from tissue using either our panel (R2=0.94, correlation =0.93) or WES (R2= 0.85, correlation=0.87), demonstrating the feasibility of assessing TMB from cfDNA using a large panel. Next, using TMB calculated from WES as gold standard, we attempted to derive a cutoff to stratify TMB high patients from TMB low patients. Our data revealed 15 mutations per mb as an optimal cutoff using the 520 panel, achieving an AUC of 97.6% for tissue samples and 97.2% for plasma samples.
8eea62084ca7e541d918e823422bd82e Conclusion
Our study demonstrated the feasibility of evaluating TMB from cfDNA using a large panel, opening the avenue of TMB estimation using liquid biopsy. Further validations in prospective clinical trials are needed to solidify its predictive value in response to immunotherapy.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.01-62 - A New Method for Non-Invasive Prediction of Radiotherapy: SDH5 Depletion Enhances Radiosensitivity by Regulating P53 (ID 12871)
12:00 - 13:30 | Presenting Author(s): Jun Liu
- Abstract
Background
Radiotherapy is an important and effective treatment for lung cancer. Some molecules can predict the effect of radiotherapy, but it is an invasive test that will cause trauma to patient. So the development of reliable non-invasive methods for predication of radiotherapy has become essential to guide therapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
We initiated an analytical, observational, open, and retrospective study (ChiCTR1800014878) of 53 patients with stage III lung adenocarcinoma who were ready for radiotherapy. The performance status (PS) scores of the patients are all over 2. Blood and tumor tissue before treatment were collected to detect SDH5 concentration. We then evaluated the prognostic role of SDH5 expression in these patients. To further verify the effect of SDH5 on radiosensitivity, two mice models (orthotopic mice bearing lung cancer and SDH5 gene knock-out mice) were established and the internal mechanism between SDH5 and radiotherapy was explored.
4c3880bb027f159e801041b1021e88e8 Result
The patients whose tumor shrink significantly one month after radiotherapy had lower expression of SDH5 in tumor, and loss of SDH5 expression correlated with down regulation of DNA-PKcsThr2609 and ku86. More importantly, SDH5 can be directly detected in blood by qRT-PCR, and the result is consistent with that in tissue. And more exciting, patients with deficiency of SDH5 had longer PFS and OS after radiotherapy, and the results in blood and in tumor are consistent. To further verify the effect of SDH5 on radiosensitivity, in vivo experiments were carried out. In the orthotopic model, SDH5 knock down tumors showed higher radiation sensitivity with smaller volume. In SDH5 knock-out mice, lung epithelial cells exhibited elevated DNA damage after radiation. Moreover, our data indicated that SDH5 depletion causes P53 translocated from cytoplasm to nucleus, which enhances radiosensitivity of non-small cell lung cancer. Furthermore, consistent with in vivo data, the tumor growth was partially reversed when p53 was co-depleted with SDH5.
8eea62084ca7e541d918e823422bd82e Conclusion
In this experiment we found that SDH5 regulated radiosensitivity by P53 and it can be detected in tumor tissue. It is a suitable marker for predicting radiosensitivity. More than this, the expression of SDH5 can be directly measured by qRT-PCR in the blood, and it is consistent with that in the tumor tissue. This provides a novel non-invasive method for predicting the radiosensitivity of the patients unable to tolerant the biopsy.
6f8b794f3246b0c1e1780bb4d4d5dc53
