Cancer-Specific Thresholds Adjust for Whole Exome Sequencing-based Tumor Mutational Burden Distribution.

Fernandez, Evan M; Eng, Kenneth; Beg, Shaham; Beltran, Himisha; Faltas, Bishoy M; Mosquera, Juan Miguel; Nanus, David M; Pisapia, David J; Rao, Rema A; Robinson, Brian D; Rubin, Mark A.; Elemento, Olivier; Sboner, Andrea; Shah, Manish A; Song, Wei (2019). Cancer-Specific Thresholds Adjust for Whole Exome Sequencing-based Tumor Mutational Burden Distribution. JCO precision oncology, 3 American Society of Clinical Oncology 10.1200/PO.18.00400

[img] Text
nihms-1046427.pdf - Accepted Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (1MB) | Request a copy

Purpose To understand the clinical context of tumor mutational burden (TMB) when comparing a pan-cancer threshold and a cancer-specific threshold. Materials and Methods Using whole exome sequencing (WES) data from primary tumors in The Cancer Genome Atlas (TCGA) (n=3,534) and advanced/metastatic tumors from Weill Cornell Medicine (WCM Advanced) (n=696), TMB status was determined using a pan-cancer and cancer-specific threshold. Survival curves, number of samples classified as TMB high, and predicted neoantigens were used to evaluate the differences between thresholds. Results The distribution of TMB varied dramatically between cancer types. A cancer-specific threshold was able to adjust for the different TMB distributions, while the pan-cancer threshold was often too stringent. The dynamic nature of the cancer-specific threshold resulted in more tumors being classified as TMB high compared to the static pan-cancer threshold. Additionally, no significant difference in survival outcomes was found with the cancer-specific threshold compared to the pan-cancer one. Further, the cancer-specific threshold maintains higher predicted neoantigen load for the TMB high samples compared to the TMB low samples, even when the threshold is lower than the pan-cancer threshold. Conclusion TMB is relative to the context of cancer type, metastatic state, and disease stage. Compared to a pan-cancer threshold, a cancer-specific threshold classifies more patients as TMB high while maintaining clinical outcomes that were not significantly different. Furthermore, the cancer-specific threshold identifies patients with a high number of predicted neoantigens. Due to the potential impact in cancer patient care, TMB status should be determined in a cancer-specific manner.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Rubin, Mark Andrew

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2473-4284

Publisher:

American Society of Clinical Oncology

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

17 Dec 2019 13:37

Last Modified:

17 Dec 2019 13:37

Publisher DOI:

10.1200/PO.18.00400

PubMed ID:

31475242

BORIS DOI:

10.7892/boris.136421

URI:

https://boris.unibe.ch/id/eprint/136421

Actions (login required)

Edit item Edit item
Provide Feedback