Abstract PR012: Targeted sequencing of 2,138 bone and soft tissue sarcomas reveals commonly altered pathways, subtype-independent genetic clusters, and potential therapeutic targets
Bibliographic record
Abstract
Abstract A hallmark of sarcomas is genetic, biologic, and clinical heterogeneity, which is a challenge for preclinical development of therapeutic targets, clinical trial design, and patient care. Because sarcomas comprise over 100 subtypes, a broad comparative genetic analysis of subtypes has been lacking and sarcoma genetic studies have by necessity focused on one or a few subtypes. We will report the results of a comprehensive analysis of somatic genetic alterations detected by a targeted sequencing platform in a single institution cohort of 2,138 patient-specific samples of soft tissue and bone sarcoma representing 45 distinct pathological entities. We determined subtype-specific mutation and copy number (arm and gene level) events with a focus on pathways in which there are therapeutic targets under clinical or preclinical investigation. The most commonly altered pathways are cell cycle control, TP53, PI3K, receptor tyrosine kinase/RAS, and epigenetic regulators (e.g. >40% of uterine leiomyosarcoma [n=165], undifferentiated pleomorphic sarcoma [UPS, n=145] and pleomorphic liposarcoma [n=22]). Subtype-specific associations in rare subtypes include TERT amplification in 41% of intimal sarcoma (n=18) and alterations in chromatin remodeling and histone modifying complexes in uterine adenosarcoma (43% and 36%, respectively; n=14). Epigenetic pathway alterations in common sarcomas were also noted, including an increased frequency of oncogenic alterations in epigenetic regulators in dedifferentiated liposarcoma (DDLS; n=167) (25%) vs. well differentiated liposarcoma (8%; n=48). We evaluated rates of whole genome doubling (WGD), which in subtypes such as UPS and osteosarcoma (n=129) were >45%, which is more frequent than many carcinomas. WGD associated with worse overall survival in metastatic (p=0.042) but not primary samples (p=0.391). Among specific subtypes, WGD was associated with worse overall survival in metastatic UPS (p=0.022). Unsupervised clustering of samples based on genetic features revealed that in some cases sarcomas are more similar to individual tumors of distinct histology than to other sarcomas of the same subtype. For example, UPS and soft tissue leiomyosarcoma (n=125) segregated into multiple genetic clusters (high entropy) compared to others with low entropy (DDLS), which could have implications for future clinical trial interpretation and/or design. We also determined the subtype-specific rate of tumor mutation burden, which was overall low compared to many carcinomas, but notably varied between and within subtypes, with some having a long tail in the upper range of the distribution. Lastly, we assessed targetable alterations on a subtype-specific basis. Together with other ‘multiomic’ approaches, we anticipate this work will motivate preclinical studies of subtype-specific sarcoma biology and potential therapeutic targets and will inform efforts to interpret outcomes in sarcoma clinical trials with respect to underlying genetic subtypes. Citation Format: Benjamin A. Nacev, Francisco Sanchez-Vega, Shaleigh Smith, Cristina Antonescu, Evan Rosenbaum, Hongyu Shi, Cerise Tang, Nicholas Socci, Satshil Rana, Rodrigo Gularte-Merida, Ahmet Zehir, Mrinal Gounder, Timothy Bowler, Anisha Luthra, Bhumika Jadeja, Azusa Okada, Jonathan Strong, Jake Stoller, Jason Chan, Ping Chi, Sandra D'Angelo, Mark Dickson, Ciara Kelly, Mary Louise Keohan, Sujana Movva, Katherine Thornton, Paul Meyers, Leonard Wexler, Emily Slotkin, Julia Glade Bender, Neerav Shukla, Martee Hensley, John Healey, Michael La Quaglia, Kaled Alektiar, Aimee Crago, Sam Yoon, Brian Untch, Sarah Chiang, Narasimhan Agaram, Meera Hameed, Michael Berger, David Solit, Nikolaus Schultz, Marc Ladanyi, Samuel Singer, William Tap. Targeted sequencing of 2,138 bone and soft tissue sarcomas reveals commonly altered pathways, subtype-independent genetic clusters, and potential therapeutic targets [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR012.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".