https://escholarship.org/content/qt5st231s3/qt5st231s3.pdf?t=omsseb

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy.

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.

Tumor mutational load predicts survival after immunotherapy across multiple cancer types.

PurposeWith prospective clinical sequencing of tumors emerging as a mainstay in cancer care, an urgent need exists for a clinical support tool that distills the clinical implications associated with specific mutation events into a standardized and easily interpretable format. To this end, we developed OncoKB, an expert-guided precision oncology knowledge base.MethodsOncoKB annotates the biologic and oncogenic effects and prognostic and predictive significance of somatic molecular alterations. Potential treatment implications are stratified by the level of evidence that a specific molecular alteration is predictive of drug response on the basis of US Food and Drug Administration labeling, National Comprehensive Cancer Network guidelines, disease-focused expert group recommendations, and scientific literature.ResultsTo date, > 3,000 unique mutations, fusions, and copy number alterations in 418 cancer-associated genes have been annotated. To test the utility of OncoKB, we annotated all genomic events in 5,98...

https://ascopubs.org/doi/pdfdirect/10.1200/PO.17.00011

OncoKB: A Precision Oncology Knowledge Base.

https://air.unimi.it/bitstream/2434/586873/2/PIIS0092867418309619.pdf

Comprehensive Characterization of Cancer Driver Genes and Mutations.

2458 Despite dramatic improvements in treatment over the past 40 years, acute lymphoblastic leukemia (ALL) remains one of the most common causes of death from disease in childhood. Glucocorticoids are among the most effective agents used in the treatment of lymphoid malignancies, and patient response to treatment is an important determinant of long-term outcome in childhood ALL. In spite of its clinical significance, the molecular basis of glucocorticoid resistance is still poorly understood. The aim of this study was to develop an experimental model system to define clinically relevant mechanisms of glucocorticoid resistance in childhood ALL. An in vivo model of childhood ALL has been developed in our laboratory, using patient biopsies established as xenografts in immune-deficient nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice. This model is highly representative of the human disease (Lock et al., Blood, 99: 4100-4108, 2002). The in vivo responses of these xenografts to the glucocorticoid dexamethasone (DEX) correlated significantly with patient outcome (p 1 μM) in xenografts from six patients, five of whom died of their disease. In contrast, four DEX-sensitive xenografts (IC50 values 2-fold in sensitive xenografts within 8 hours of treatment. In contrast, Bim induction was dramatically attenuated in DEX-resistant xenografts. These results have identified a clinically significant and novel mechanism of glucocorticoid resistance in childhood ALL, which occurs downstream of receptor-ligand interactions, but upstream of the signalling pathway resulting in Bim induction and apoptosis.

Novel mechanisms of glucocorticoid resistance in childhood acute lymphoblastic leukemia.

BACKGROUND
Next-generation sequencing in cancer research may reveal germline variants of clinical significance. We report patient preferences for return of results and the prevalence of incidental pathogenic germline variants (PGVs).


PATIENTS AND METHODS
Targeted exome sequencing of 202 genes was carried out in 1000 advanced cancers using tumor and normal DNA in a research laboratory. Pathogenic variants in 18 genes, recommended for return by The American College of Medical Genetics and Genomics, as well as PALB2, were considered actionable. Patient preferences of return of incidental germline results were collected. Return of results was initiated with genetic counseling and repeat CLIA testing.


RESULTS
Of the 1000 patients who underwent sequencing, 43 had likely PGVs: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2 (1), and RB1 (1). Twenty (47%) of 43 variants were previously known based on clinical genetic testing. Of the 1167 patients who consented for a germline testing protocol, 1157 (99%) desired to be informed of incidental results. Twenty-three previously unrecognized mutations identified in the research environment were confirmed with an orthogonal CLIA platform. All patients approached decided to proceed with formal genetic counseling; in all cases where formal genetic testing was carried out, the germline variant of concern validated with clinical genetic testing.


CONCLUSIONS
In this series, 2.3% patients had previously unrecognized pathogenic germline mutations in 19 cancer-related genes. Thus, genomic sequencing must be accompanied by a plan for return of germline results, in partnership with genetic counseling.

Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol.


 Background: Clonal hematopoiesis (CH) is identified as the presence of clonal populations of hematopoietic stem cells (HSC). Hematopoietic lineage differentiation is subjected to genetic mutations that, due to fitness advantages, might give rise to clonally expanded populations. Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the outgrowth of a single clone driven by acquired somatic mutation(s) in HSCs, in the absence of hematological abnormalities. Previous studies have been shown the association of CH with aging and a higher risk of developing secondary hematologic malignancies in cancer patients treated with chemotherapy agents. It is therefore of great interest to study CH incidence prior to and post chemotherapy exposure and its association with the evolution of hematologic malignancies. We aimed to characterize CHIP variants of a highly selected group of patients with high-grade serous ovarian cancer (HGSC) who underwent neoadjuvant chemotherapy; moreover, while previous CHIP studies are largely knowledge based and are limited to known hematologic genes or target gene panels, our study discovers novel CHIP mutations.
 Methods: Comprehensive ultra-high-depth whole exome sequencing using unique molecular barcode technologies was performed using plasma-derived cell-free DNA and matched white blood cells DNA and tumor DNA from pre-NACT (n=12) and post-NACT (n=12) samples of patients with HGSC who have excellent or poor response to NACT. Using spike-in mutated DNAs as positive controls, we detected variant alleles at 1% variant allele frequency.
 Results: We identified on average about 3,000 candidate CHIP variants in one patient. Among these, 1,977 variants affecting 1,375 genes were recurrently found in more than one patient. These CHIP genes include not only previous reported CHIP genes (e.g. DNMT3A, JAK2, TET2, and KMT2D) but also many novel CHIP candidates (such as RPTN, MTCH2, FAM186A, CACNA1A, FCGBP, and MUC3A). A number of CHIP mutations were uniquely found enriched in post-chemotherapy samples (e.g. ARID1A T290P, TP53 G245D, SMARCA4 G495D, and CIC T2456P). Interestingly, there is a strong enrichment of COSMIC cancer census genes in CHIP genes identified in every patient.
 Conclusions: Our findings corroborate the notion that CHIP mutations are present in nonmalignant blood cells of patients with HGSC, and some are enriched after chemotherapy. Moreover, our innovative sequencing approach allowed discovery of novel candidate CHIP genes. The systematic identification of CHIP in patients with HGSC might be an important new clinical consideration when establishing chemotherapy protocols.
 Citation Format: Sara Corvigno, Jun Yao, Li Zhao, Amma Asare, Joseph Celestino, Richard Hajek, Ency Arboleda Goette, Elaine Stur, Emine Bayraktar, Mark S Kim, Ping Song, Qingxiu Zhang, Xingzhi Song, Mohammad Mohammad, Kenna Shaw, Jianhua Zhang, Karen Lu, Amir Jazaeri, Shannon Westin, Sanghoon Lee, Anil Sood. Genomic profiling of chemotherapy-related clonal hematopoiesis in patients with high-grade serous ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5473.

Abstract 5473: Genomic profiling of chemotherapy-related clonal hematopoiesis in patients with high-grade serous ovarian cancer

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Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol.

Abstract 5473: Genomic profiling of chemotherapy-related clonal hematopoiesis in patients with high-grade serous ovarian cancer