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Germline mutations in PARK2 are a well-known cause of the neurodegenerative disorder Parkinson's disease. Here, Timothy Chan and colleagues report somatic mutations and intragenic deletions of PARK2 in glioblastoma, colon cancer and lung cancer. Mutation of the gene PARK2 , which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease 1 , 2 , 3 . In a search for multisite tumor suppressors, we identified PARK2 as a frequently targeted gene on chromosome 6q25.2–q27 in cancer. Here we describe inactivating somatic mutations and frequent intragenic deletions of PARK2 in human malignancies. The PARK2 mutations in cancer occur in the same domains, and sometimes at the same residues, as the germline mutations causing familial Parkinson's disease. Cancer-specific mutations abrogate the growth-suppressive effects of the PARK2 protein. PARK2 mutations in cancer decrease PARK2's E3 ligase activity, compromising its ability to ubiquitinate cyclin E and resulting in mitotic instability. These data strongly point to PARK2 as a tumor suppressor on 6q25.2–q27. Thus, PARK2 , a gene that causes neuronal dysfunction when mutated in the germline, may instead contribute to oncogenesis when altered in non-neuronal somatic cells.

Tyrosine phosphorylation plays a critical role in regulating cellular function and is a central feature in signaling cascades involved in oncogenesis. The regulation of tyrosine phosphorylation is coordinately controlled by kinases and phosphatases (PTPs). Whereas activation of tyrosine kinases has been shown to play vital roles in tumor development, the role of PTPs is much less well defined. Here, we show that the receptor protein tyrosine phosphatase delta (PTPRD) is frequently inactivated in glioblastoma multiforme (GBM), a deadly primary neoplasm of the brain. PTPRD is a target of deletion in GBM, often via focal intragenic loss. In GBM tumors that do not possess deletions in PTPRD, the gene is frequently subject to cancer-specific epigenetic silencing via promoter CpG island hypermethylation (37%). Sequencing of the PTPRD gene in GBM and other primary human tumors revealed that the gene is mutated in 6% of GBMs, 13% of head and neck squamous cell carcinomas, and in 9% of lung cancers. These mutations were deleterious. In total, PTPRD inactivation occurs in >50% of GBM tumors, and loss of expression predicts for poor prognosis in glioma patients. Wild-type PTPRD inhibits the growth of GBM and other tumor cells, an effect not observed with PTPRD alleles harboring cancer-specific mutations. Human astrocytes lacking PTPRD exhibited increased growth. PTPRD was found to dephosphorylate the oncoprotein STAT3. These results implicate PTPRD as a tumor suppressor on chromosome 9p that is involved in the development of GBMs and multiple human cancers.

Distinct genes are mutated in different regions of a single patient’s tumor. Point mutations seem to have less adverse effect on relapse-free survival than copy-number heterogeneity. Chromosome instability appears to be an important adverse prognostic factor. Lung cancer is the leading cause of cancer-related death worldwide, 1 , 2 with non–small-cell lung cancer (NSCLC) being the most common type. Large-scale sequencing studies have revealed the complex genomic landscape of NSCLC 3 – 6 and genomic differences between lung adenocarcinomas and lung squamous-cell carcinomas. 7 However, in-depth exploration of NSCLC intratumor heterogeneity (which provides the fuel for tumor evolution and drug resistance) and cancer genome evolution has been limited to small retrospective cohorts. 8 , 9 Therefore, the clinical significance of intratumor heterogeneity and the potential for clonality of driver events to guide therapeutic strategies have not yet been defined. Tracking Non–Small-Cell Lung Cancer . . .

Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape 1 – 5 . However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-sequencing (RNA-seq) data with spatial histology mapped by deep learning in 100 patients with non-small cell lung cancer from the TRACERx cohort 6 . Cancer subclones derived from immune cold regions were more closely related in mutation space, diversifying more recently than subclones from immune hot regions. In TRACERx and in an independent multisample cohort of 970 patients with lung adenocarcinoma, tumors with more than one immune cold region had a higher risk of relapse, independently of tumor size, stage and number of samples per patient. In lung adenocarcinoma, but not lung squamous cell carcinoma, geometrical irregularity and complexity of the cancer–stromal cell interface significantly increased in tumor regions without disruption of antigen presentation. Decreased lymphocyte accumulation in adjacent stroma was observed in tumors with low clonal neoantigen burden. Collectively, immune geospatial variability elucidates tumor ecological constraints that may shape the emergence of immune-evading subclones and aggressive clinical phenotypes. Multiregion spatial histology, exome and transcriptome data from patients with non-small cell lung cancer suggest that cancer subclones from immune cold regions diversify later than subclones from immune hot regions

Approximately 50% of patients with early-stage non-small-cell lung cancer (NSCLC) who undergo surgery with curative intent will relapse within 5 years1,2. Detection of circulating tumor cells (CTCs) at the time of surgery may represent a tool to identify patients at higher risk of recurrence for whom more frequent monitoring is advised. Here we asked whether CellSearch-detected pulmonary venous CTCs (PV-CTCs) at surgical resection of early-stage NSCLC represent subclones responsible for subsequent disease relapse. PV-CTCs were detected in 48% of 100 patients enrolled into the TRACERx study3, were associated with lung-cancer-specific relapse and remained an independent predictor of relapse in multivariate analysis adjusted for tumor stage. In a case study, genomic profiling of single PV-CTCs collected at surgery revealed higher mutation overlap with metastasis detected 10 months later (91%) than with the primary tumor (79%), suggesting that early-disseminating PV-CTCs were responsible for disease relapse. Together, PV-CTC enumeration and genomic profiling highlight the potential of PV-CTCs as early predictors of NSCLC recurrence after surgery. However, the limited sensitivity of PV-CTCs in predicting relapse suggests that further studies using a larger, independent cohort are warranted to confirm and better define the potential clinical utility of PV-CTCs in early-stage NSCLC.Pulmonary venous tumor cells disseminating before tumor resection are heterogeneous, predict relapse and seed future metastasis of lung cancer

Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.A survey of T cell repertoire evolution in the tumors, healthy tissue and blood of patients with early-stage untreated lung cancer offers an opportunity to monitor and identify neoantigen-specific T cells for personalized immunotherapy.

Timothy Chan and colleagues show that the PARK2 tumor suppressor is a master regulator of G1 and S phase cyclins and is critical for proper cell cycle regulation. PARK2 genetic alterations are common across many human cancers as well as in hereditary Parkinson's disease. Coordinate control of different classes of cyclins is fundamentally important for cell cycle regulation and tumor suppression, yet the underlying mechanisms are incompletely understood. Here we show that the PARK2 tumor suppressor mediates this coordination. The PARK2 E3 ubiquitin ligase coordinately controls the stability of both cyclin D and cyclin E. Analysis of approximately 5,000 tumor genomes shows that PARK2 is a very frequently deleted gene in human cancer and uncovers a striking pattern of mutual exclusivity between PARK2 deletion and amplification of CCND1 , CCNE1 or CDK4 —implicating these genes in a common pathway. Inactivation of PARK2 results in the accumulation of cyclin D and acceleration of cell cycle progression. Furthermore, PARK2 is a component of a new class of cullin-RING–containing ubiquitin ligases targeting both cyclin D and cyclin E for degradation. Thus, PARK2 regulates cyclin-CDK complexes, as does the CDK inhibitor p16, but acts as a master regulator of the stability of G1/S cyclins.

An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage1. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types2–6. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.TRACERx Lung: Intratumoral transcriptional heterogeneity, which often hinders the development of clinically useful RNA-expression-biased biomarkers for cancer, can now be overcome with an approach for the identification of clonal expression biomarkers.

Background Apple juice is considered to be an important component of the healthy diet, with anticancer activities in colon cancer animal models and key ingredients have numerous chemoprotective activities in human colon cells in vitro. Aim of the study Since only little is known on comparable activities in the human colon in vivo, here a pilot study was performed to assess related mechanisms caused by ileostomy samples from volunteers that had consumed apple juice. Methods Ileostomy samples were collected after intervention (0–8 h) with cloudy apple juice (1 l). They were characterized analytically for major apple polyphenols and biologically in HT29 colon cells for their potential to cause genotoxic damage, protect from the genotoxic insult by hydrogen peroxide (H 2 O 2 ) and modulate the expression of GSTT2, an enzyme related to antioxidative defence against different peroxides. Results The analytical determination of polyphenols in the ileostomy samples revealed that the majority of the compounds were recovered in the samples collected 2 h after intervention. The comparison of genotoxic effects of samples before intervention and 2 h after intervention revealed a considerable variation of genotoxic response, but there was a trend for reduced genotoxicity in three of eight persons (P) after intervention. Samples collected at 2 h protected HT29 cells from genotoxic damage by H 2 O 2 (for 4 of 8 persons), resulted in an increased GSTT2 expression (for 2 of 6 persons) and of GSTT2 promotor activity (2 of 6 persons). Conclusions The intervention with apple juice results in bioavailable concentrations of related polyphenols in the gut lumen, which could contribute to reduced genotoxicity, enhanced antigenotoxicity and favorable modulation of GSTT2 gene expression in some individuals. The pilot study for the first time used this combination of faecal biomarkers which in larger cohorts may either reveal overall significant alterations of chemoprotection or may be used to identify individuals which could particularly benefit from a personalized nutrition.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.