The Christie School of Oncology: Christie Research Publications Repository
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Replication-associated mechanisms contribute to an increased CpG > TpG mutation burden in mismatch repair-deficient cancers
No full textBACKGROUND: Single base substitution (SBS) mutations, particularly C > T and T > C, are increased owing to unrepaired DNA replication errors in mismatch repair-deficient (MMRd) cancers. Excess CpG > TpG mutations have been reported in MMRd cancers defective in mismatch detection (dMutSα), but not in mismatch correction (dMutLα). Somatic CpG > TpG mutations conventionally result from unrepaired spontaneous deamination of 5'-methylcytosine throughout the cell cycle, causing T:G mismatches and signature SBS1. It has been proposed that MutSα detects those mismatches, prior to error correction by base excision repair (BER). However, other evidence appears inconsistent with that hypothesis: for example, MutSα is specifically expressed in S/G(2) phases of the cell cycle, and defects in replicative DNA polymerase proofreading specifically cause excess CpG > TpG mutations in signature SBS10b. METHODS: We analysed mutation spectra and COSMIC mutation signatures in whole-genome sequencing data from 1803 colorectal cancers (164 dMutLα, 20 dMutSα) and 596 endometrial cancers (103 dMutLα, 9 dMutSα) from the UK 100,000 Genomes Project. We mapped each C > T mutation to its genomic features, including normal DNA methylation state, replication timing, transcription strand, and replication strand, to investigate the mechanism(s) by which these mutations arise. RESULTS: We confirmed that dMutSα tumours specifically had higher CpG > TpG burdens than dMutLα tumours. We could fully reconstitute the observed dMutSα CpG > TpG mutation spectrum by adding CpG > TpG mutations in proportion to their SBS1 activity to the dMutLα spectrum. However, other evidence indicated that the SBS1 excess in dMutSα cancers did not come from 5'-methylcytosine deamination alone: non-CpG C > T mutations were also increased in dMutSα cancers; and, in contrast to tumours deficient in BER, CpG > TpG mutations were biased to the leading DNA replication strand, at similar levels in dMutSα and dMutLα cancers, suggesting an origin in DNA replication. Other substitution mutations usually corrected by BER were not increased in dMutSα tumours. CONCLUSIONS: There is a CpG > TpG and SBS1 excess specific to dMutSα MMRd tumours, consistent with previous reports, and we find a general increase in somatic C > T mutations. Contrary to some other studies, the similar leading replication strand bias in both dMutSα and dMutLα tumours indicates that at least some of the excess CpG > TpG mutations arise via DNA replication errors, and not primarily via the replication-independent deamination of 5'-methylcytosine
Defining a consensus post-operative clinical target volume (CTV) for thymic epithelial tumours (TET): a contouring exercise by the BTOG thymic malignancies special interest group
No full textDeveloping a nurse led clinic to deliver vorasidinib - practicalities, patients and outcomes
No full textImpact of bone protecting agents (BPA) on the efficacy and safety of enzalutamide vs. combination of radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): sub-goup analysis from EORTC-GUCG 1333/PEACE-3, an EORTC/CTI/CUOG/LACOG/UNICANCER randomized phase III study
No full textInsights into the cellular lipid cascade of prostate cells explored using infrared microspectroscopy
No full textBackground: Although prostate cancer (PCa) is the most diagnosed cancer in men worldwide, there is geographical variance in both incidence and morbidity, with higher levels in developed 'Western Diet' countries. In particular the high levels of the omega-6 polyunsaturated fatty acid, arachidonic acid (AA), in Western diets has been shown to promote aggressive PCa in vitro. However the exact mechanism through which AA induces the aggressive phenotype has not been fully characterised. Methods: In this study Fourier transform infrared (FTIR) imaging coupled with fluorescence microscopy (FM), is used to follow AA metabolism in PCa cell lines. This is achieved using partially deuterated AA, with a distinctive C-D stretch seen at 2251 cm(-1) providing molecular specificity, coupled with Nile Red Fluorescence imaging. Results: We show that, invasive cell lines PC-3, LNCaP C4-2B and DU145 readily uptake and metabolise AA, producing prostaglandins via the COX-2 pathway. Inhibition of the COX-2 pathway with either NS938 or the omega-3 polyunsaturated fatty acid Docosahexaenoic acid (DHA), reduces the invasive stimulus of AA and blocks its uptake. Conclusion: This demonstrates that FTIR imaging can be utilised to follow metabolomics processes within a PCa model and provide an insight to the molecular pathways underlying the cancer metabolome. Additionally, these works provide key insights into the rapid uptake of AA within certain invasive cell lines of prostate cancer, suggesting that AA exposure initiates early cellular responses prior to the uptake and processing of lipids within the cells
Should radiation dose be personalized in patients with localized NSCLC and actionable genetic alterations? insight from a multicenter real-world study
No full textOBJECTIVES: Radiation therapy (RT) is central to the management of unresectable stage I to III NSCLC. However, the impact of actionable genetic driver alterations (AGAs) on locoregional control (LRC) from RT remains uncertain. A retrospective, multicenter real-world study was undertaken to determine if common AGAs impact LRC after RT. METHODS: Patients who received curative-intent RT for NSCLC between 2018 and 2020 at four centers in the United Kingdom and had available molecular testing were included. Locoregional control was compared in a 1:2 ratio between a group of patients with an AGA and a control group without AGAs. Locoregional control was assessed with competing risks analysis and overall survival was analyzed by Cox regression, adjusting for established prognostic clinical factors. RESULTS: Data was collected for 185 eligible patients: 50 with an AGA and 135 without. Baseline characteristics, including patient demographics, tumor features, and treatment details were evenly distributed between the two groups. LRC was similar in the AGA and non-AGA groups (39% versus 34%, hazard ratio = 1.13, 95% confidence interval: 0.61-1.984, p = 0.84). Actionable genetic driver alterations were not associated with LRC according to multivariable regression analysis. Median overall survival was significantly higher in the AGA group (45 mo versus 26 mo, hazard ratio = 0.64, 95% confidence interval: 0.43-0.96, p = 0.044), and all these patients received targeted therapies on relapse. CONCLUSION: LRC was comparable in the AGA and non-AGA groups suggesting that there is no role for personalization of RT dose solely due to the detection of an AGA. Nevertheless, survival rates were notably higher among patients with AGAs, likely owing to the availability of efficacious targeted therapies on relapse
Targeting c-MYC and gain-of-function p53 through inhibition or degradation of the kinase LZK suppresses the growth of HNSCC tumors
No full textThe worldwide annual frequency and lethality of head and neck squamous cell carcinoma (HNSCC) is not improving, and thus, new therapeutic approaches are needed. Approximately 70% of HNSCC cases have either amplification or overexpression of MAP3K13, which encodes the kinase LZK. Here, we found that LZK is a therapeutic target in HNSCC and that small-molecule inhibition of its catalytic function decreased the viability of HNSCC cells with amplified MAP3K13. Inhibition of LZK suppressed tumor growth in MAP3K13-amplified xenografts derived from HNSCC patients. LZK stabilized the transcription factor c-MYC through its kinase activity and gain-of-function mutants of p53 in a kinase-independent manner. We designed a proteolysis-targeting chimera (PROTAC) that induced LZK degradation, leading to decreased abundance of both c-MYC and gain-of-function p53, and reduced the viability of HNSCC cells. Our findings demonstrate that LZK-targeted therapeutics, particularly PROTACs, may be effective in treating HNSCCs with MAP3K13 amplification
Real world experience of glofitamab and epcoritamab: a retrospective UK multicentre analysis
No full textP-Rex1 limits the agonist-induced internalization of GPCRs independently of its Rac-GEF activity
No full textThe guanine-nucleotide exchange factor (GEF) P-Rex1 mediates G protein-coupled receptor (GPCR) signaling by activating the small GTPase Rac. We show here that P-Rex1 also controls GPCR trafficking. P-Rex1 inhibits the agonist-stimulated internalization of the GPCR S1PR1 independently of its Rac-GEF activity, through its PDZ, DEP, and inositol polyphosphate 4-phosphatase domains. P-Rex1 also limits the agonist-induced trafficking of CXCR4, PAR4, and GLP1R but does not control steady-state GPCR levels, nor the agonist-induced internalization of the receptor tyrosine kinases PDGFR and EGFR. P-Rex1 blocks the phosphorylation required for GPCR internalization. P-Rex1 binds G protein-coupled receptor kinase 2 (Grk2), both in vitro and in cells, but does not appear to regulate Grk2 activity. We propose that P-Rex1 limits the agonist-induced internalization of GPCRs through its interaction with Grk2 to maintain high levels of active GPCRs at the plasma membrane. Therefore, P-Rex1 plays a dual role in promoting GPCR responses by controlling GPCR trafficking through an adapter function as well as by mediating GPCR signaling through its Rac-GEF activity
Prognostic significance of PTEN loss in prostate cancer: a meta-analysis of gleason grade and clinical outcomes
No full textAIMS: Prostate cancer (PCa) presents ongoing challenges in differentiating aggressive from indolent disease using traditional biomarkers such as prostate-specific antigen (PSA). The Phosphatase and Tensin Homolog (PTEN), a key tumour suppressor involved in cellular growth regulation, is emerging as a promising biomarker for risk stratification. This meta-analysis aims to evaluate the prognostic significance of PTEN loss in PCa, particularly its relationship with Gleason grade groups (GG), as defined by the ISUP system, and clinical outcomes. METHODS: A systematic review and meta-analysis of 16 studies encompassing 11,375 patients was conducted in accordance with PRISMA guidance. Studies included evaluated PTEN loss, stratified by hemizygous and homozygous deletions, and its association with GG and clinical endpoints such as biochemical recurrence and lethal progression. Pooled odds ratios (ORs) and hazard ratios (HRs) were calculated using a random-effects model. RESULTS: PTEN loss was significantly associated with tumour aggressiveness. Compared to GG1 tumours, the odds of PTEN loss were markedly increased in Gleason GG 2 and 3(OR: 2.78, 95% CI: 1.95-3.61) and GG ≥ 4 (OR: 6.35, 95% CI: 5.37-7.33). Homozygous PTEN deletions were more strongly associated with high-grade tumours than hemizygous deletions. Clinically, PTEN loss was predictive of adverse outcomes, including increased risk of biochemical recurrence (HR: 1.78, 95% CI: 1.31-2.25) and lethal progression (HR: 2.57, 95% CI: 1.12-3.95). CONCLUSION: PTEN loss correlates with higher GG and poorer clinical outcomes in PCa. Incorporating PTEN assessment into clinical decision making could improve risk stratification, guiding early intervention strategies and identifying patients suitable for active surveillance