Drugs targeting the cell cycle-regulatory cyclin-dependent kinase (CDK) 4 and 6 have been approved for the treatment of hormone receptor-positive breast cancer, and inhibitors targeting other ...cell-cycle CDKs are currently in clinical trials. Another class of CDKs, the transcription-associated CDKs, including CDK7, CDK8, CDK9, CDK12 and CDK13, are critical regulators of gene expression. Recent evidence suggests several novel functions of these CDKs, including regulation of epigenetic modifications, intronic polyadenylation, DNA-damage responses, and genomic stability. Here, we summarize our current understanding of the transcriptional CDKs, their utility as biomarkers, and their potential as therapeutic targets. SIGNIFICANCE: CDK inhibitors targeting CDK4 and CDK6 have been approved in hormone receptor-positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Several studies now point to potential therapeutic opportunities by inhibiting the transcription-associated CDKs as well as therapeutic vulnerabilities with PARP inhibitors and immunotherapy in tumors deficient in these CDKs.
As epithelial tumors grow from single cells to a malignant mass of invasive tissue, they must exploit the innate inflammatory response, while evading the adaptive immune system. Prognosis of solid ...tumors has historically focused on macroscopic features such as size, grade, and mitotic index. It is now clear that prognosis assessment must also consider the stromal and immune cells that surround and infiltrate the tumor. Tumors promote growth, angiogenesis, and tissue remodeling by subverting the normal functions of macrophages and other cells of the innate immune system that inhabit their microenvironment. Simultaneously, tumor cells escape from and inactivate the adaptive immune system by exploiting the mechanisms preventing damaging auto-immune responses in cytotoxic T cells. The presence of CD8+ T cells within epithelial tumors is now a well-supported marker of better prognosis in many tumor types. However, this benefit is counterbalanced by immune regulatory cell populations that promote tumor escape from immune surveillance and metastasis. Therapeutic approaches that kill tumor cells selectively by re-activating immune checkpoints are becoming an established therapeutic option, but it is not yet clear how to identify which patients will benefit from this treatment modality. Evidence is accumulating that identifying the presence of T cell-activating neoantigens, produced by mutated proteins in tumors, will play an important role in checkpoint inhibitor prognosis. This review provides an overview of the evidence that lymphocytic infiltration of tumors has prognostic value in many epithelial tumor types and is linked to the success of chemical and immune checkpoint therapeutic strategies.
•The presence of tumor-infiltrating lymphocytes is a positive prognostic marker in many solid tumors, including breast, colon, and melanoma.•Both pathological review of tissue sections and gene transcription analysis effectively quantify lymphocytic infiltrate.•The role of tumor-infiltrating lymphocytes in breast cancer is mediated by the tumor's molecular subtype.•Patients whose tumors bear a higher somatic mutational burden are more likely to benefit from immune checkpoint inhibitors.
Next-generation sequencing of human tumours has refined our understanding of the mutational processes operative in cancer initiation and progression, yet major questions remain regarding the factors ...that induce driver mutations and the processes that shape mutation selection during tumorigenesis. Here we performed whole-exome sequencing on adenomas from three mouse models of non-small-cell lung cancer, which were induced either by exposure to carcinogens (methyl-nitrosourea (MNU) and urethane) or by genetic activation of Kras (Kras(LA2)). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the Kras(LA2) model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single-nucleotide variants, compared with only six in tumours from the Kras(LA2) model. By contrast, the Kras(LA2) tumours exhibited a significantly higher level of aneuploidy and copy number alterations compared with the carcinogen-induced tumours, suggesting that carcinogen-induced and genetically engineered models lead to tumour development through different routes. The wild-type allele of Kras has been shown to act as a tumour suppressor in mouse models of non-small-cell lung cancer. We demonstrate that urethane-induced tumours from wild-type mice carry mostly (94%) Kras Q61R mutations, whereas those from Kras heterozygous animals carry mostly (92%) Kras Q61L mutations, indicating a major role for germline Kras status in mutation selection during initiation. The exome-wide mutation spectra in carcinogen-induced tumours overwhelmingly display signatures of the initiating carcinogen, while adenocarcinomas acquire additional C > T mutations at CpG sites. These data provide a basis for understanding results from human tumour genome sequencing, which has identified two broad categories of tumours based on the relative frequency of single-nucleotide variations and copy number alterations, and underline the importance of carcinogen models for understanding the complex mutation spectra seen in human cancers.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Immunological memory is thought to depend on a stem cell-like, self-renewing population of lymphocytes capable of differentiating into effector cells in response to antigen re-exposure. Here we ...describe a long-lived human memory T cell population that has an enhanced capacity for self-renewal and a multipotent ability to derive central memory, effector memory and effector T cells. These cells, specific to multiple viral and self-tumor antigens, were found within a CD45RO(-), CCR7(+), CD45RA(+), CD62L(+), CD27(+), CD28(+) and IL-7Rα(+) T cell compartment characteristic of naive T cells. However, they expressed large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, and showed numerous functional attributes distinctive of memory cells. Compared with known memory populations, these lymphocytes had increased proliferative capacity and more efficiently reconstituted immunodeficient hosts, and they mediated superior antitumor responses in a humanized mouse model. The identification of a human stem cell-like memory T cell population is of direct relevance to the design of vaccines and T cell therapies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Summary
Resistance to two classes of FDA-approved therapies that target DNA repair-deficient tumors is caused by mutations that restore the tumor cell's DNA repair function. Identifying ...these “reversion” mutations currently requires manual annotation of patient tumor sequence data. Here we present AARDVARK, an R package that automatically identifies reversion mutations from DNA sequence data.
Availability and implementation
AARDVARK is implemented in R (≥3.5). It is available on GitHub at https://github.com/davidquigley/aardvark. It is licensed under the MIT license.
Adaptive T-cell immunity relies on the recruitment of antigen-specific clonotypes, each defined by the expression of a distinct T-cell receptor (TCR), from an array of naïve T-cell precursors. ...Despite the enormous clonotypic diversity that resides within the naïve T-cell pool, interindividual sharing of TCR sequences has been observed within mobilized T-cell responses specific for certain peptide–major histocompatibility complex (pMHC) antigens. The mechanisms that underlie this phenomenon have not been fully elucidated, however. A mechanism of convergent recombination has been proposed to account for the occurrence of shared, or “public,” TCRs in specific memory T-cell populations. According to this model, TCR sharing between individuals is directly related to TCR production frequency; this, in turn, is determined on a probabilistic basis by the relative generation efficiency of particular nucleotide and amino acid sequences during the recombination process. Here, we tested the key predictions of convergent recombination in a comprehensive evaluation of the naïve CD8⁺ TCRβ repertoire in mice. Within defined segments of the naïve CD8⁺ T-cell repertoire, TCRβ sequences with convergent features were (i) present at higher copy numbers within individual mice and (ii) shared between individual mice. Thus, the naïve CD8⁺ T-cell repertoire is not flat, but comprises a hierarchy of recurrence rates for individual clonotypes that is determined by relative production frequencies. These findings provide a framework for understanding the early mobilization of public CD8⁺ T-cell clonotypes, which can exert profound biological effects during acute infectious processes.
In breast cancer, the TP53 gene is frequently mutated and the mutations have been associated with poor prognosis. The prognostic impact of the different types of TP53 mutations across the different ...molecular subtypes is still poorly understood. Here, we characterize the spectrum and prognostic significance of TP53 mutations with respect to the PAM50 subtypes and integrative clusters (IC).
TP53 mutation status was obtained for 1,420 tumor samples from the METABRIC cohort by sequencing all coding exons using the Sanger method.
TP53 mutations were found in 28.3% of the tumors, conferring a worse overall and breast cancer-specific survival HR = 2.03; 95% confidence interval (CI), 1.65-2.48, P < 0.001, and were also found to be an independent marker of poor prognosis in estrogen receptor-positive cases (HR = 1.86; 95% CI, 1.39-2.49, P < 0.001). The mutation spectrum of TP53 varied between the breast cancer subtypes, and individual alterations showed subtype-specific association. TP53 mutations were associated with increased mortality in patients with luminal B, HER2-enriched, and normal-like tumors, but not in patients with luminal A and basal-like tumors. Similar observations were made in ICs, where mutation associated with poorer outcome in IC1, IC4, and IC5. The combined effect of TP53 mutation, TP53 LOH, and MDM2 amplification on mortality was additive.
This study reveals that TP53 mutations have different clinical relevance in molecular subtypes of breast cancer, and suggests diverse roles for TP53 in the biology underlying breast cancer development.
Computer vision may aid in melanoma detection.
We sought to compare melanoma diagnostic accuracy of computer algorithms to dermatologists using dermoscopic images.
We conducted a cross-sectional ...study using 100 randomly selected dermoscopic images (50 melanomas, 44 nevi, and 6 lentigines) from an international computer vision melanoma challenge dataset (n = 379), along with individual algorithm results from 25 teams. We used 5 methods (nonlearned and machine learning) to combine individual automated predictions into “fusion” algorithms. In a companion study, 8 dermatologists classified the lesions in the 100 images as either benign or malignant.
The average sensitivity and specificity of dermatologists in classification was 82% and 59%. At 82% sensitivity, dermatologist specificity was similar to the top challenge algorithm (59% vs. 62%, P = .68) but lower than the best-performing fusion algorithm (59% vs. 76%, P = .02). Receiver operating characteristic area of the top fusion algorithm was greater than the mean receiver operating characteristic area of dermatologists (0.86 vs. 0.71, P = .001).
The dataset lacked the full spectrum of skin lesions encountered in clinical practice, particularly banal lesions. Readers and algorithms were not provided clinical data (eg, age or lesion history/symptoms). Results obtained using our study design cannot be extrapolated to clinical practice.
Deep learning computer vision systems classified melanoma dermoscopy images with accuracy that exceeded some but not all dermatologists.
Endometrioid ovarian carcinoma (EOVC) is an uncommon subtype of epithelial ovarian carcinoma and its molecular characteristics have been incompletely described. Prior sequencing investigations have ...been limited to targeted gene panels. We performed whole-exome sequencing to build an unbiased genetic profile of molecular alterations in endometrioid ovarian tumors with a goal to better understand this disease in the context of epithelial ovarian cancer and endometrioid uterine cancers.
Whole-exome sequencing was performed on EOVC samples (n = 26) and matched normals (n = 15). Gene mutations, mutational signatures and copy number variations (CNVs) informed a multi-dimensional regression classifier allowing for comparison to endometrial carcinoma (UCEC) and high grade serous ovarian carcinoma (HGSC).
EOVC has a distinct and heterogeneous genomic profile. Identified significantly mutated genes in EOVC (PTEN, CTNNB1, PIK3CA, KMT2D, KMT2B, PIK3R1, ARID1A and TP53) occurred at similar frequencies in UCEC. Hypermutation, resulting from both mismatch repair deficiency (MMRd) and POLE mutation, was observed in EOVC at a frequency similar to UCEC. Like UCEC, a subset of EOVC cases closely resembled HGSC, harboring TP53 mutations, homologous recombination deficiency (HRd) mutation signatures and widespread CNVs. A machine-learning classifier confirmed the heterogeneous composition of EOVC. Potential therapeutic targets were identified in 62% of EOVC cases. We validated our findings in an orthogonal clinical sequencing registry of EOVC cases.
We identified that EOVC are a molecularly heterogeneous group of epithelial ovarian cancers with distinct mutational signatures. In an age of precision oncology, there is a pressing need to understand the unique molecular drivers in uncommon histologic subtypes to facilitate genomically driven oncologic treatments.
•Endometrioid ovarian carcinoma (EOVC) has a distinct, heterogeneous genomic profile.•EOVC is molecularly similar to endometrial carcinoma.•Some EOVCs harbor whole genome doubling events and present at a later stage.•EOVC harbors multiple therapeutic dependencies.
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