We discuss This adds to the current evidence that SOX11 is a gene involved in palatogenesis.
◥Collagen remodeling contributes to many physiologic and pathologic processes. In primary tumors, the linearization of collagen fibers promotes cancer cell invasion and metastasis and is indicative of poor prognosis. However, it remains unknown whether there are endogenous inhibitors of collagen linearization that could be exploited therapeutically. Here, we show that collagen linearization is controlled by two secreted matricellular proteins with antagonistic functions. Specifically, WISP1 was secreted by cancer cells, bound to type I collagen (Col I), and linearized Col I via its cysteine-rich C-terminal (CT) domain. In contrast, WISP2, which lacks a CT domain, inhibited Col I linearization by preventing WISP1-Col I binding. Analysis of patient data revealed that WISP2 expression is lower in most solid tumors, in comparison with normal tissues. Consequently, genetic or pharmacologic restoration of higher WISP2 levels impaired collagen linearization and prevented tumor cell invasion and metastasis in vivo in models of human and murine breast cancer. Thus, this study uncovers WISP2 as the first inhibitor of collagen linearization ever identified and reveals that collagen architecture can be normalized and metastasis inhibited by therapeutically restoring a high WISP2:
This collaborative essay, structured as a collection of tales akin to Chaucer's, provides a multiperspectival reflection on enhancement study days, entitled 'Chaucer's World', co-organised by the University of Oxford, the Ashmolean Museum, the Bodleian Library, and secondary schools from the area. The event is aimed at UK secondary school students in their final two years of study, and is intended not only to help students with their preparation for the A-Level English Literature exam but also to instil in them appreciation for Chaucer's works, as well as for medieval literature and culture in general.
Introduction Lung cancer is the most common cause of cancer-related death. Carcinogenic and endogenous processes driving somatic mutation acquisition in cancer can be extracted and defined as mutational signatures using whole genome sequencing (WGS). Tobacco smoke is the main aetiological cause of lung cancer, with mutational signature 4 representing the characteristic C>A transversions produced by smoking. Whilst smoking cessation has been shown to reduce lung cancer risk in epidemiological studies, there has been little exploration into the persistence of smoking 4 in NSCLC genomes after a patient has quit smoking. We investigated the extent and persistence of signature 4 in NSCLC genomes of current, ex- and never-smokers, correlating in particular with clinical history of smoking cessation. Methods 132 NSCLC samples were resected from 131 patients in Greater Manchester. These samples were submitted to the 100,000 Genomes Project (Genomics England). WGS was performed on tumour specimens and matched blood samples. Data generated was processed by a standard pipeline devised by Genomics England. Tumour mutational burden (TMB), mutational signatures and copy number variation (CNV) were obtained. Clinical data collected included: smoking status, date of diagnosis, TNM stage, date of relapse and date of death (where relevant). Fisher's exact tests and Kruskal-Wallis tests were used for statistical comparisons, with Kaplan-Meier plots for survival. Results Signature 4 was associated with a smoking history in 102/119 (85.7%) NSCLCs with a detailed smoking history available. In 17/119 (14.3%) patients with a smoking history but no signature 4 NSCLC, 15/17 (88.2%) patients quit smoking a median of 22 years ago (range 0.006 - 45 years). 6/7 (85.7%) never-smoker NSCLCs were non-signature 4 NSCLCs. 60/75 (80%) ex-smokers had sufficient smoking data to assess signature 4 persistence. Signature 4 endured in the lung tissue prior to tumour diagnosis for a median of 180 months (15 years) (range 1 - 600 months). There was no association between the time of smoking cessation and the time to NSCLC diagnosis (R2=0.0009, p=0.82). Non-signature 4 NSCLCs had a more diverse signature profile (signature 4: mean 4.36, 95% CI 4.13-4.58; non-signature 4: mean 5.52, 95% CI 4.95-6.09; p=<0.0001) with a lower TMB (signature 4: median 9.76/Mb, 95% CI 9.8-12.7; non-signature 4: median 2.02/Mb, 95% CI 1.3-9.3; p=<0.0001). There was no difference in relapse-free survival between signature 4 and non-signature 4 patients with early stage disease (signature 4: median 456 days, HR 0.999, 95% CI 0.419-2.385; non-signature 4: median 319 days, HR 1.001, 95% CI 0.417-2.399). Conclusion The genomic alterations introduced by smoking persist for many years after smoking cessation. NSCLCs arising from smoking carry a distinctive identity compared to those from never-smokers, with higher TMBs driven primarily by signature 4. Whilst survival analysis is limited in this cohort, the pervasive contributions from smoking suggest that lung cancer screening programmes should include all patients with a smoking history. Citation Format: Pantelis A. Nicola, Shereen Rafee, George Burghel, Andrew Wallace, Helene Schlecht, Eleanor Baker, Katie Baker, Lynsey Priest, Mathew Carter, Sharzad Moghadam, Jane Rogan, Robert G. Bristow, William Newman, Fiona H. Blackhall, Colin Lindsay. Persistence of smoking signature 4 in the non-small cell lung cancer genome [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3810.
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Introduction: Kirsten rat sarcoma viral oncogene (KRAS) is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), occurring in approximately 30% of cases. Recent work suggests KRAS -mutant (KRASm) NSCLC is a microcosm for diverse immune checkpoint inhibitor responses, partly dictated by its co-mutation with TP53 (“KP” group=~1/3 cases, “immune hot”), STK11 (“KL” group=~1/3 cases, “immune cold”) or CDKN2A (“KC” group=~1/3 cases). Here we identify and describe genomic and clinical associations of a further subset of KRASm NSCLC defined by “triple WT” status for common KRASm co-mutations. Method: Sequencing results from 364 early-stage NSCLC cases from the Cancer Research UK TRACERx program (whole-exome sequencing) and the Genomics England 100,000 genome program (whole-genome sequencing) were analyzed for KRASm, associated co-mutations in TP53, STK11 and CDKN2A, copy number changes in the RAS-RAF-MEK-ERK axis, tumor mutational burden (TMB) and mutational signatures. Clinical demographics and factors including tumor size, nodal status and stage were ascertained and assessed for statistical associations with sequencing data using the Mann-Whitney and Fisher’s exact tests. Results: Overall, 143/364 lung cancer cases (39%) were KRASm with 65/143 (45%) tumors identified as “KP,” 26/143 (18%) as “KL,” and 3/143 (2%) as “KC.” There were 49/143 KRASm cases (34%) with no co-mutation in TP53, STK11 or CDKN2A, defined as “triple wild-type” (triple WT). Relative to the KP, KL and KC genotypes, there was a positive association of the KRAS G12D mutation with triple WT status: 10/49 cases, 20%; KP/KL/KC: 6/94 cases, 6%; p=0.022). In the 100,000-genome cohort, TMB was similar for the triple WT and KL groups but significantly lower than that observed for KP (KP: median 10.55 mut/Mb, 95% CI 8.8-15.33; triple WT: median 6.96, 95% CI 4.87-12.53; p=0.036). Despite this lower median TMB, smoking-associated mutational signature 4 was common in triple WT tumors (triple WT: 13/14 pts, 93%; overall 76/114 pts, 67%). In the triple WT group overall, there was a reduction of >50% in cancers with copy number changes of NF1 and NRAS. There was an inverse association between pathologic stage III tumors and KRASm triple WT genotype (p=0.0014). Conclusion: There are a significant proportion of KRASm NSCLC patients whose tumors are triple WT for TP53, STK11 and CDKN2A. Despite their high frequency of smoking-associated mutational signatures, these tumors are characterized by low TMB and are more common in early-stage disease. They also associate more commonly with KRAS G12D. Our observations suggest a discrete KRASm subset that may have implications for stratification in trials of immune checkpoint inhibitors and/or targeted therapeutics of KRASm tumors. Citation Format: Colin R. Lindsay, Pantelis Nicola, Mariam Jamal-Hanjani, Andrew Wallace, Gareth Wilson, George Burghel, Helene Schlecht, Katie Baker, Eleanour Baker, Lynsey Priest, Jane Rogan, Sharzad Moghadam, Mathew Carter, Caroline Dive, Robert G. Bristow, Charles Swanton, William Newman, Fiona Blackhall. “Triple wild-type” co-mutational profile in early-stage KRAS-mutant lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B49.
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