Abstract Focal amplifications (FA) can mediate targeted therapy resistance in cancer. Understanding the structure and dynamics of FAs is critical for designing treatments that overcome plasticity-mediated resistance. We developed a melanoma model of dual MAPK inhibitor (MAPKi) resistance that bears BRAFV600 amplifications through either extrachromosomal DNA (ecDNA)/double minutes (DM) or intrachromosomal homogenously staining regions (HSR). Cells harboring BRAFV600E FAs displayed mode switching between DMs and HSRs, from both de novo genetic changes and selection of preexisting subpopulations. Plasticity is not exclusive to ecDNAs, as cells harboring HSRs exhibit drug addiction–driven structural loss of BRAF amplicons upon dose reduction. FA mechanisms can couple with kinase domain duplications and alternative splicing to enhance resistance. Drug-responsive amplicon plasticity is observed in the clinic and can involve other MAPK pathway genes, such as RAF1 and NRAS. BRAF FA-mediated dual MAPKi–resistant cells are more sensitive to proferroptotic drugs, extending the spectrum of ferroptosis sensitivity in MAPKi resistance beyond cases of dedifferentiation. Significance: Understanding the structure and dynamics of oncogene amplifications is critical for overcoming tumor relapse. BRAF amplifications are highly plastic under MAPKi dosage challenges in melanoma, through involvement of de novo genomic alterations, even in the HSR mode. Moreover, BRAF FA-driven, dual MAPKi–resistant cells extend the spectrum of resistance-linked ferroptosis sensitivity. This article is highlighted in the In This Issue feature, p. 873
Stemness is defined as the potential of cells for self-renewal and differentiation. Many transcriptome-based methods for stemness evaluation have been proposed. However, all these methods showed low negative correlations with differentiation time and can't leverage the existing experimentally validated stem cells to recognize the stem-like cells.
The clinical applicability of the whole-exome sequencing (WES) in estimating tumor mutational burden (TMB) is currently limited by high cost, time-consuming and tissue availability.And given to the differences in the mutational landscapes among different types of cancer, we aimed to develop a cancer-specific signature to estimate TMB for right-sided colon cancer patients (RCC).Using WES data of 315 RCC patients, we identified the exons in which the number of mutational sites of the coding DNA sequences associated with TMB through linear regression analysis.Then, among these exons, we extracted a signature composed by 102 exons (~0.13 Mbp) through a heuristic selection procedure.The TMB estimated by the signature was highly correlated with those calculated by WES in the discovery dataset (R 2 =0.9869) and three independent validation datasets (R 2 =0.9351,R 2 =0.8063 and R 2 =0.9527, respectively).And the performance of the signature was superior to a colorectal-specific TMB estimation model contained 22 genes (~0.24 Mbp).Moreover, between TMB-high and TMB-low RCC patients, there were significantly differences in the frequencies of microsatellite instability status, CpG island methylator phenotype, BRAF, KRAS and POLE/POLD1 mutation status (p<0.01).However, the performances of the signature in other types of cancer were dramatically degraded (left-sided colon cancer, R 2 =0.7849 and 0.9407, respectively; rectum, R 2 =0.5955 and R 2 =0.965, respectively; breast cancer, R 2 =0.8444; lung cancer, R 2 =0.5963), suggesting that it was necessary to develop cancer-specific TMB estimated signatures to estimate precisely the TMB in different types of cancer.In summary, we developed an exon signature that can accurately estimate TMB in RCC patients, and the cost and time required for the assessment of TMB can be considerably decreased, making it more suitable for blood and/or biopsy samples.
Table S3 Four hundred and twenty-seven oysters collected from the world-wide scale and their phenotyping values, including the content of glycogen, protein, and 17 different amino acids. (XLSX 66 kb)
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