Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling ...of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions.
Summary
Solanum lycopersicum (tomato) and its wild relatives harbor genetic diversity that yields heritable variation in fruit chemistry that could be exploited to identify genes regulating their ...synthesis and accumulation. Carotenoids, for example, are essential in plant and animal nutrition, and are the visual indicators of ripening for many fruits, including tomato. Whereas carotenoid synthesis is well characterized, factors regulating flux through the pathway are poorly understood at the molecular level. To exploit the impact of tomato genetic diversity on carotenoids, Solanum pennellii introgression lines were used as a source of defined natural variation and as a resource for the identification of candidate regulatory genes. Ripe fruits were analyzed for numerous fruit metabolites and transcriptome profiles generated using a 12 000 unigene oligoarray. Correlation analysis between carotenoid content and gene expression profiles revealed 953 carotenoid‐correlated genes. To narrow the pool, subnetwork analysis of carotenoid‐correlated transcription revealed 38 candidates. One candidate for impact on trans‐lycopene and β‐carotene accumulation was functionally charaterized, SlERF6, revealing that it indeed influences carotenoid biosynthesis and additional ripening phenotypes. Reduced expression of SlERF6 by RNAi enhanced both carotenoid and ethylene levels during fruit ripening, demonstrating an important role for SlERF6 in ripening, integrating the ethylene and carotenoid synthesis pathways.
Pathways regulating threonine, methionine and isoleucine metabolism are very efficiently interconnected in plants. As both threonine and methionine serve as substrates for isoleucine synthesis, their ...synthesis and catabolism under different developmental and environmental conditions also influence isoleucine availability. Together, methionine gamma-lyase and threonine deaminase maintain the isoleucine equilibrium in plants under varied substrate availabilities. Isoleucine and the two other branched-chain amino acids (BCAAs) (leucine and valine) share four common enzymes in their biosynthesis pathways and thus are coordinately regulated. Induction of free amino acids as osmolytes in response to abiotic stress is thought to play a role in plant stress tolerance. In particular, the accumulation of BCAAs is induced many-fold during osmotic stress. However, unlike in the case of proline, not much research has been focused on understanding the function of the response involving BCAAs. This review describes pathways influencing branched-chain amino acid metabolism and what is known about the biological significance of their accumulation under abiotic stress. A bioinformatics approach to understanding the transcriptional regulation of the genes involved in amino acid metabolism under abiotic stress is also presented.
Abstract
Choosing an optimal concomitant drug for combination with poly‐ADP ribose polymerase (PARP) inhibitor based on patient‐specific biomarker status may help increase to improve treatment ...efficacy in patients with ovarian cancer. However, the efficacy and safety of different PARP inhibitor‐based combinations in patients with homologous recombination repair (HRR) mutations have not been evaluated in ovarian cancer. In this sub‐study of Korean Gynecologic Oncology Group (KGOG) 3045, we compared the efficacy and safety of two olaparib‐based combinations and biomarkers of patients with platinum‐resistant ovarian cancer with HRR gene mutations. Patients were randomized to receive either olaparib (200 mg twice a day) + cediranib (30 mg daily) (Arm 1, n = 16) or olaparib (300 mg) + durvalumab (1,500 mg once every 4 weeks) (Arm 2, n = 14). The objective response rates for Arm 1 and Arm 2 were 50.0% and 42.9%, respectively. Most patients (83.3%) had
BRCA
mutations, which were similarly distributed between arms. Grade 3 or 4 treatment‐related adverse events were observed in 37.5% and 35.7% of the patients, respectively, but all were managed properly. A high vascular endothelial growth factor signature was associated with favorable outcomes in Arm 1, whereas immune markers (PD‐L1 expression CPS ≥10, CD8, neutrophil‐to‐lymphocyte ratio and platelet‐to‐lymphocyte ratio) were associated with favorable outcomes in Arm 2. The activation of homologous recombination pathway upon disease progression was associated with poor response to subsequent therapy. Based on comprehensive biomarker profiling, including immunohistochemistry, whole‐exome and RNA sequencing and whole blood‐based analyses, we identified biomarkers that could help inform which of the two combination strategies is appropriate given a patient's biomarker status. Our findings have the potential to improve treatment outcome for patients with ovarian cancer in the PARP inhibitor era.
Purpose
This study investigated the correlations between parameters of
18
F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) scan and indices of genetic properties, heterogeneity ...index (HI), and tumor mutation burden (TMB), in patients with lung cancer.
Methods
We produced 106 PET indices for each tumor site that underwent genomic analysis in a total of 176 study subjects (age, 62.0 ± 10.0 y; males, 68.2%), comprising 101 adenocarcinoma (ADC), 29 squamous cell carcinoma (SQCC), and 46 small cell lung cancer (SCLC) patients. We then examined the correlations of the PET parameters with genetic properties of HI and TMB, according to pathology and tumor site.
Results
Comparisons between PET parameters and the genetic properties with false discovery rate (FDR) correction revealed that the surface standard uptake value (SUV) entropy of SUV statistics had a significant correlation with HI only in patients with SCLC who underwent a genetic test in lymph nodes (
r
= 0.592,
p
= 0.028), whereas PET parameters did not show a significant correlation with HI or TMB in patients with SCLC who underwent a genetic test in lung tissue. In patients with ADC and SQCC, there was no significant correlation between PET parameters and the genetic properties. Although SUV
max
showed raw
p
values less than 0.05 in correlation with HI (
r
= 0.315, raw
p
= 0.048) and TMB (
r
= 0.206, raw
p
= 0.043) in ADC, and SUV
peak
had a raw
p
value less than 0.05 in correlation with HI (
r
= 0.394, raw
p
= 0.046) in SQCC, these parameters were not significant when corrected by FDR.
Conclusions
In this study, surface SUV entropy had a significant correlation with HI in SCLC. Regarding other PET parameters and tumors, no significant correlation with genetic parameters existed.
Tumors continuously evolve to maintain growth; secondary mutations facilitate this process, resulting in high tumor heterogeneity. In this study, we compared mutations in paired primary and ...metastatic colorectal cancer tumor samples to determine whether tumor heterogeneity can predict tumor metastasis.
Somatic variations in 46 pairs of matched primary-liver metastatic tumors and 42 primary tumors without metastasis were analyzed by whole-exome sequencing. Tumor clonality was estimated from single-nucleotide and copy-number variations. The correlation between clinical parameters of patients and clonal heterogeneity in liver metastasis was evaluated.
Tumor heterogeneity across colorectal cancer samples was highly variable; however, a high degree of tumor heterogeneity was associated with a worse disease-free survival. Highly heterogeneous primary colorectal cancer was correlated with a higher rate of liver metastasis. Recurrent somatic mutations in
, and
were frequently detected in highly heterogeneous colorectal cancer. The variant allele frequency of these mutations was high, while somatic mutations in other genes such as
and
were low. The number and distribution of primary colorectal cancer subclones were preserved in metastatic tumors.
Heterogeneity of primary colorectal cancer tumors can predict the potential for liver metastasis and thus, clinical outcome of patients.
.
Tumor genetic heterogeneity may underlie poor clinical outcomes because diverse subclones could be comprised of metastatic and drug resistant cells. Targeted deep sequencing has been used widely as a ...diagnostic tool to identify actionable mutations in cancer patients. In this study, we evaluated the clinical utility of estimating tumor heterogeneity using targeted panel sequencing data. We investigated the prognostic impact of a tumor heterogeneity (TH) index on clinical outcomes, using mutational profiles from targeted deep sequencing data acquired from 1,352 patients across 8 cancer types. The TH index tended to be increased in high pathological stage disease in several cancer types, indicating clonal expansion of cancer cells as tumor progression proceeds. In colorectal cancer patients, TH index values also correlated significantly with clinical prognosis. Integration of the TH index with genomic and clinical features could improve the power of risk prediction for clinical outcomes. In conclusion, deep sequencing to determine the TH index could serve as a promising prognostic indicator in cancer patients.
Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor ...cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.
Accurate detection of genomic alterations using high-throughput sequencing is an essential component of precision cancer medicine. We characterize the variant allele fractions (VAFs) of somatic ...single nucleotide variants and indels across 5095 clinical samples profiled using a custom panel, CancerSCAN. Our results demonstrate that a significant fraction of clinically actionable variants have low VAFs, often due to low tumor purity and treatment-induced mutations. The percentages of mutations under 5% VAF across hotspots in EGFR, KRAS, PIK3CA, and BRAF are 16%, 11%, 12%, and 10%, respectively, with 24% for EGFR T790M and 17% for PIK3CA E545. For clinical relevance, we describe two patients for whom targeted therapy achieved remission despite low VAF mutations. We also characterize the read depths necessary to achieve sensitivity and specificity comparable to current laboratory assays. These results show that capturing low VAF mutations at hotspots by sufficient sequencing coverage and carefully tuned algorithms is imperative for a clinical assay.
PDF
