Claudins (CLDNs) are central components of tight junctions that regulate epithelial-cell barrier function and polarity. Altered CLDN expression patterns have been demonstrated in numerous cancer types and lineage-specific CLDNs have been proposed as therapy targets. The objective of this study was to assess which fraction of patients with non-small-cell lung cancer (NSCLC) express CLDN6 and CLDN18 isoform 2 (CLDN18.2). Protein expression of CLDN6 and CLDN18.2 was examined by immunohistochemistry on a tissue microarray (n 5 355) and transcript levels were supportively determined based on gene expression microarray data from fresh-frozen NSCLC tissues (n 5 196). Both were analyzed with regard to frequency, distribution and association with clinical parameters. Immunohistochemical analysis of tissue sections revealed distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) proteins in virtually non-overlapping subgroups of adenocarcinomas and large-cell carcinomas. Pneumocytes and bronchial epithelial cells were consistently negative. Corresponding to the protein expression, in subsets of non-squamous lung carcinoma high mRNA levels of CLDN6 (7-16%) and total CLDN18 (5-12%) were observed. Protein expression correlated well with total mRNA expression of the corresponding gene (rho 5 0.4-0.8). CLDN18.2 positive tumors were enriched among slowly proliferating, thyroid transcription factor 1 (TTF-1)-negative adenocarcinomas, suggesting that isoform-specific CLDN expression may delineate a specific subtype. Noteworthy, high CLDN6 protein expression was associated with worse prognosis in lung adenocarcinoma in the univariate [hazard ratio (HR): 1.8; p 5 0.03] and multivariate COX regression model (HR: 1.9; p 5 0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC.Non-small-cell lung cancer (NSCLC) therapy has changed dramatically as the comprehensive molecular analysis of lung cancer specimens has identified multiple, clinically relevant driver aberrations. Many of these aberrations can be targeted by specific inhibitors previously developed for the treatment of other cancer types.1,2 Indication extension of such drug

Since the publication of the original paper, the authors realized in the analyses of day 15 MRD <25% and day 29 MRD data and outcome, three patients were misclassified due to non-censoring of event after HSCT. All three were stratified concordantly by FCM and PCR, two above (one relapse and one non-relapse related death) and one (relapse) below the cutoff level of 10 −3 . There is no change in the conclusions of the paper. An additional seven were misclassified but had day 15 MRD levels >0.25 and thus did not affect further analyses.The original article can be found online at https://doi.org/10.1038/ s41375-018-0307-6. 1234567890();,:1234567890();,:

The online version of this article has a Supplementary Appendix. BackgroundThe existence of multiple subsets of chronic lymphocytic leukemia expressing 'stereotyped' Bcell receptors implies the involvement of antigen(s) in leukemogenesis. Studies also indicate that 'stereotypy' may influence the clinical course of patients with chronic lymphocytic leukemia, for example, in subsets with stereotyped IGHV3-21 and IGHV4-34 B-cell receptors; however, little is known regarding the genomic profile of patients in these subsets. Design and MethodsWe applied 250K single nucleotide polymorphism-arrays to study copy-number aberrations and copy-number neutral loss-of-heterozygosity in patients with stereotyped IGHV3-21 (subset #2, n=29), stereotyped IGHV4-34 (subset #4, n=17; subset #16, n=8) and non-subset #2 IGHV3-21 (n=13) and non-subset #4/16 IGHV4-34 (n=34) patients. ResultsOver 90% of patients in subset #2 and non-subset #2 carried copy-number aberrations, whereas 75-76% of patients in subset #4 and subset #16 showed copy-number aberrations. Subset #2 and non-subset #2 patients also displayed a higher average number of aberrations compared to patients in subset #4. Deletion of 13q was the only known recurrent aberration detected in subset #4 (35%); this aberration was even more frequent in subset #2 (79%). del(11q) was more frequent in subset #2 and non-subset #2 (31% and 23%) patients than in subset #4 and nonsubset #4/16 patients. Recurrent copy-number neutral loss-of-heterozygosity was mainly detected on chromosome 13q, independently of B-cell receptor stereotypy. ConclusionsGenomic aberrations were more common in subset #2 and non-subset #2 than in subset #4. The particularly high frequency of del(11q) in subset #2 may be linked to the adverse outcome reported for patients in this subset. Conversely, the lower prevalence of copy-number aberrations and the absence of poor-prognostic aberrations in subset #4 may reflect an inherently low-proliferative disease, which would prevent accumulation of genomic alterations.Key words: chronic lymphocytic leukemia, stereotyped B-cell receptors, antigens, leukemogenesis. 'stereotyped' IGHV3-21 and IGHV4-34 B-cell receptors. Haematologica 2010;95(9):1519-1525. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Marincevic M, Cahill N, Gunnarsson R, Isaksson A, Mansouri M, Göransson H, Rasmussen M, Jansson M, Ryan F, Karlsson K, Adami H-O, Davi F, Jurlander J, Juliusson G, Stamatopoulos K, and Rosenquist R. High-density screening reveals a different spectrum of genomic aberrations in chronic lymphocytic leukemia patients withHigh-density screening reveals a different spectrum of genomic aberrations in chronic lymphocytic leukemia patients with 'stereotyped' IGHV3-21 and IGHV4-34 B-cell receptors

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The online version of this article has a Supplementary Appendix. BackgroundNumerous subsets of patients with chronic lymphocytic leukemia display similar immunoglobulin gene usage with almost identical complementarity determining region 3 sequences. Among IGHV4-34 cases, two such subsets with "stereotyped" B-cell receptors were recently identified, i.e. subset #4 (IGHV4-34/IGKV2-30) and subset #16 (IGHV4-34/IGKV3-20). Subset #4 patients appear to share biological and clinical features, e.g. young age at diagnosis and indolent disease, whereas little is known about subset #16 at a clinical level. Design and MethodsWe investigated the global gene expression pattern in sorted chronic lymphocytic leukemia cells from 25 subset/non-subset IGHV4-34 patients using Affymetrix gene expression arrays. ResultsAlthough generally few differences were found when comparing subset to non-subset 4/16 IGHV4-34 cases, distinct gene expression profiles were revealed for subset #4 versus subset #16. The differentially expressed genes, predominantly with lower expression in subset #4 patients, are involved in important cell regulatory pathways including cell-cycle control, proliferation and immune response, which may partly explain the low-proliferative disease observed in subset #4 patients. ConclusionsOur novel data demonstrate distinct gene expression profiles among patients with stereotyped IGHV4-34 B-cell receptors, providing further evidence for biological differences in the pathogenesis of these subsets and underscoring the functional relevance of subset assignment based on B-cell receptor sequence features.Key words: stereotyped BCR, IGHV4-34, chronic lymphocytic leukemia, gene expression. IGHV4-34 B-cell receptors. Haematologica 2010;95(12):2072-2079. doi:10.3324/haematol.2010 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Citation: Marincevic M, Mansouri M, Kanduri M, Isaksson A, Göransson H, Smedby KE, Jurlander J, Juliusson G, Davi F, Stamatopoulos K, and Rosenquist R. Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors