High expression of the vacuole membrane protein 1 (VMP1) is a potential marker of poor prognosis in HER2 positive breast cancer.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBACKGROUND: Fusion genes result from genomic structural changes, which can lead to alterations in gene expression that supports tumor development. The aim of the study was to use fusion genes as a tool to identify new breast cancer (BC) genes with a role in BC progression. METHODS: Fusion genes from breast tumors and BC cell lines were collected from publications. RNA-Seq data from tumors and cell lines were retrieved from databanks and analyzed for fusions with SOAPfuse or the analysis was purchased. Fusion genes identified in both tumors (n = 1724) and cell lines (n = 45) were confirmed by qRT-PCR and sequencing. Their individual genes were ranked by selection criteria that included correlation of their mRNA level with copy number. The expression of the top ranked gene was measured by qRT-PCR in normal tissue and in breast tumors from an exploratory cohort (n = 141) and a validation cohort (n = 277). Expression levels were correlated with clinical and pathological factors as well as the patients' survival. The results were followed up in BC cohorts from TCGA (n = 818) and METABRIC (n = 2509). RESULTS: Vacuole membrane protein 1 (VMP1) was the most promising candidate based on specific selection criteria. Its expression was higher in breast tumor tissue than normal tissue (p = 1x10-4), and its expression was significantly higher in HER2 positive than HER2 negative breast tumors in all four cohorts analyzed. High expression of VMP1 associated with breast cancer specific survival (BCSS) in cohort 1 (hazard ratio (HR) = 2.31, CI 1.27-4.18) and METABRIC (HR = 1.26, CI 1.02-1.57), and also after adjusting for HER2 expression in cohort 1 (HR = 2.03, CI 1.10-3.72). BCSS was not significant in cohort 2 or TCGA cohort, which may be due to differences in treatment regimens. CONCLUSIONS: The results suggest that high VMP1 expression is a potential marker of poor prognosis in HER2 positive BC. Further studies are needed to elucidate how VMP1 could affect pathways supportive of tumorigenesis

Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts : results from the population-based iStopMM study

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been associated with other medical conditions. Since systematic screening is not recommended, MGUS is typically diagnosed due to underlying diseases and most cases are not diagnosed. Most previous studies on MGUS disease associations have been based on clinical cohorts, possibly resulting in selection bias. Here we estimate this selection bias by comparing clinically diagnosed and screened individuals with MGUS with regards to demographics, laboratory features, and comorbidities. A total of 75,422 participants in the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS by serum protein electrophoresis, immunofixation and free light chain assay (clinicaltrials gov. Identifier: NCT03327597). We identified 3,352 individuals with MGUS, whereof 240 had previously been clinically diagnosed (clinical MGUS), and crosslinked our data with large, nationwide registries for information on comorbidities. Those with clinical MGUS were more likely to have at least one comorbidity (odds ratio=2.24; 95% confidence interval: 1.30-4.19), and on average had more comorbidities than the screened MGUS group (3.23 vs. 2.36, mean difference 0.68; 95% confidence interval: 0.46-0.90). They were also more likely to have rheumatological disease, neurological disease, chronic kidney disease, liver disease, heart failure, or endocrine disorders. These findings indicate that individuals with clinical MGUS have more comorbidities than the general MGUS population and that previous studies have been affected by significant selection bias. Our findings highlight the importance of screening data when studying biological and epidemiological implications of MGUS.Peer reviewe

Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r(2) = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10(-32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10(-7)).National Cancer Research Institute (NCRI) G0500966/75466 Department of Health, Medical Research Council Cancer Research UK University of Cambridge NIHR Department of Health Anniversary Fund of the Austrian National Bank 15079 Medical and Scientific Fund of the Mayor of the City of Vienna 10077 Common Fund of the Office of the Director of the National Institutes of Health NCI NHGRI NHLBI NIDA NIMH NINDS NCI\SAIC-Frederick, Inc. (SAIC-F) 10XS170 Roswell Park Cancer Institute 10XS171 Science Care, Inc. X10S172 SAIC-F 10ST1035 HHSN261200800001E deCODE genetics/AMGEN HHSN268201000029C DA006227 DA033684 N01MH000028 MH090941 MH101814 MH090951 MH090937 MH101820 MH101825 MH090936 MH101819 MH090948 MH101782 MH101810 MH10182

Defining new reference intervals for serum free light chains in individuals with chronic kidney disease : Results of the iStopMM study

Publisher Copyright: © 2022. The Author(s). © 2022. The Author(s).Serum free light chain (FLC) concentration is greatly affected by kidney function. Using a large prospective population-based cohort, we aimed to establish a reference interval for FLCs in persons with chronic kidney disease (CKD). A total of 75422 participants of the iStopMM study were screened with serum FLC, serum protein electrophoresis and immunofixation. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Central 99% reference intervals were determined, and 95% confidence intervals calculated. Included were 6461 (12%) participants with measured FLCs, eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, and without evidence of monoclonality. Using current reference intervals, 60% and 21% had kappa and lambda FLC values outside the normal range. The FLC ratio was outside standard reference interval (0.26-1.65) in 9% of participants and outside current kidney reference interval (0.37-3.10) in 0.7%. New reference intervals for FLC and FLC ratio were established. New reference intervals for the FLC ratio were 0.46-2.62, 0.48-3.38, and 0.54-3.30 for eGFR 45-59, 30-44, and < 30 mL/min/1.73 m2 groups, respectively. The crude prevalence of LC-MGUS in CKD patients was 0.5%. We conclude that current reference intervals for FLC and FLC ratio are inaccurate in CKD patients and propose new eGFR based reference intervals to be implemented.Peer reviewe

Histopathology and levels of proteins in plasma associate with survival after colorectal cancer diagnosis

Funding Information: The authors thank the subjects who have donated their time and their samples that were used in this research. Publisher Copyright: © 2023, The Author(s).Background: The TNM system is used to assess prognosis after colorectal cancer (CRC) diagnosis. Other prognostic factors reported include histopathological assessments of the tumour, tumour mutations and proteins in the blood. As some of these factors are strongly correlated, it is important to evaluate the independent effects they may have on survival. Methods: Tumour samples from 2162 CRC patients were visually assessed for amount of tumour stroma, severity of lymphocytic infiltrate at the tumour margins and the presence of lymphoid follicles. Somatic mutations in the tumour were assessed for 2134 individuals. Pre-surgical levels of 4963 plasma proteins were measured in 128 individuals. The associations between these features and prognosis were inspected by a Cox Proportional Hazards Model (CPH). Results: Levels of stroma, lymphocytic infiltration and presence of lymphoid follicles all associate with prognosis, along with high tumour mutation burden, high microsatellite instability and TP53 and BRAF mutations. The somatic mutations are correlated with the histopathology and none of the somatic mutations associate with survival in a multivariate analysis. Amount of stroma and lymphocytic infiltration associate with local invasion of tumours. Elevated levels of two plasma proteins, CA-125 and PPP1R1A, associate with a worse prognosis. Conclusions: Tumour stroma and lymphocytic infiltration variables are strongly associated with prognosis of CRC and capture the prognostic effects of tumour mutation status. CA-125 and PPP1R1A may be useful prognostic biomarkers in CRC.Peer reviewe

Bronchiolitis obliterans organizing pneumonia (BOOP). A clinico-pathologic study

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenThe diagnosis of BOOP is based on characteristic changes on lung biopsy in patients with a variety of symptoms and radiographic changes. We studied nineteen patients, ten males and nine females, with biopsy proven BOOP. The most common clinical findings were fever, shortness of breath and non-productive cough for less than eight weeks and inspiratory crackles on auscultation. Laboratory tests often revealed increased erythrocyte sedimentation rate, low grade anemia, moderate increase in white blood cell count and arterial hypoxemia. Irregular alveolar infiltrates were the most common radiographic abnormalities. Open lung biopsy was required in three. Seven patients in our study were considered to have idiopathic or primary BOOP with no identifiable cause. Twelve patients had either an underlying bacterial lung infection, rheumatologic disease or cancer. Thirteen patients received corticosteroid treatment, usually oral prednisolone at an initial dose of 30-60 mg/day, for a variable length of time. Predisolone treatment resulted in recovery with clearing of lung infiltrates in all patients but one, who died of myocardial infarction five days after treatment was begun. However relapses occurred in more than half (57%) of those receiving prednisolone. Relapses usually occurred when the prednisolone doses had been reduced below 15 mg/day, and in patients who had been treated for up to 10 months. Recovery ensued when perdnisolone doses were increased. Four patients recovered after treatment with antibiotics alone. BOOP probably represents a non-specific inflammatory response of the lung to a number of insults. The high proportion of cases with an established underlying disease in our study is unique. Our data also suggest that infection may be the most frequent underlying condition in BOOP. Corticosteroids were effective treatment but relapses were common. A thorough search for an underlying disease is warranted, and if recognized, should be treated accordingly.Bandvefsmyndandi berkjungateppa með lungnabólgu (Bronchiolitis Obliterans Organizing Pneumonia - BOOP) er sjúkdómsgreining byggð á sérkennandi vefjabreytingum í lungum, sem fyrst var lýst af Lange árið 1901 (1). Á undanförnum áratug hefur orðið ljóst að þessum breytingum fylgja oft sérkennandi sjúkdómseinkenni og breytingar á röntgenmynd (2,3)- BOOP hefur því í vaxandi mæli verið skilgreind sem sérstakt sjúkdómsástand. Þessi áhersla á BOOP sem sjálfstæðan sjúkdóm hefur hagnýta þýðingu, því að BOOP hefur svarað barksterameðferð mun betur en aðrir bandvefsmyndandi bólgusjúkdómar í lungum. Í fyrri rannsóknum hefur í fæstum tilfellum fundist orsök fyrir BOOP-breytingum og sjúkdómurinn því talinn vera af óþekktum orsökum (2-7). Það er þó vel þekkt að BOOP-breytingar greinast í tengslum við aðra sjúkdóma, svo sem sýkingar, liðagigt, krabbamein, geislun og fleira (8-10)

Comparison of diagnosis and treatment of invasive breast cancer between Iceland and Sweden

TILGANGUR Rannsóknin var liður í innleiðingu gæðaskráningar brjóstakrabbameina á Íslandi og markmiðið að bera saman greiningu og meðferð ífarandi brjóstakrabbameina á Íslandi og í Svíþjóð. EFNIVIÐUR OG AÐFERÐIR Upplýsingar um alla einstaklinga sem greindust með ífarandi brjóstakrabbamein á Íslandi 2016-2017 fengust frá Krabbameinsskrá. Breytur úr sjúkraskrám voru skráðar í eyðublöð í Heilsugátt að fyrirmynd sænsku gæðaskráningarinnar og voru niðurstöður bornar saman við niðurstöður fyrir ífarandi brjóstakrabbamein af heimasíðu sænsku krabbameinsskrárinnar. Notað var tvíhliða kí-kvaðrat-próf til að bera saman hlutföll. NIÐURSTÖÐUR Á rannsóknartímabilinu greindust 486 ífarandi brjóstakrabbamein á Íslandi og 15.325 í Svíþjóð. Hlutfallslega færri 40-69 ára konur greindust við hópleit á Íslandi (46%) en í Svíþjóð (60%) (p<0,01). Á Íslandi voru haldnir heldur færri samráðsfundir fyrir fyrstu meðferð (92%) og eftir aðgerð (96%) miðað við Svíþjóð árið 2016 (98% og 99%) (p<0,05) en ekki var marktækur munur 2017. Varðeitlataka var gerð í 69% aðgerða á Íslandi en í 94% aðgerða í Svíþjóð (p<0,01). Ef æxlið var ≤30 mm var á Íslandi gerður fleygskurður í 48% tilvika en í 80% tilvika í Svíþjóð (p<0,01). Á Íslandi fengu 87% geislameðferð eftir fleygskurð en 94% í Svíþjóð (p<0,01). Ef eitlameinvörp greindust í brottnámsaðgerð þá fengu 49% geislameðferð eftir aðgerð á Íslandi en 83% í Svíþjóð (p<0,01). ÁLYKTANIR Marktækur munur er á ýmsum þáttum greiningar og meðferðar ífarandi brjóstakrabbameina milli Íslands og Svíþjóðar. Með gæðaskráningu brjóstakrabbameina á Íslandi er hægt að fylgjast með og setja markmið um ákveðna þætti greiningar og meðferðar í því skyni að veita sem flestum einstaklingum bestu meðferð. PURPOSE: As part of the implementation of quality registration in Iceland we used retrospective data to compare diagnosis and treatment of invasive breast cancer between Iceland and Sweden. MATERIALS AND METHODS: Information on all patients diagnosed with invasive breast cancer in Iceland 2016-2017 was obtained from the Icelandic Cancer Registry. Hospital records were used to register variables in an electronic form adapted from the Swedish quality registration, and compared with data from Sweden for the same period. A chi-square test was used to compare ratios. RESULTS: A total of 486 cases of breast cancer were diagnosed in Iceland and 15.325 in Sweden. A lower proportion of 40-69 year old women were diagnosed within the screening programme in Iceland (46%) compared to Sweden (60%) (p<0.01). Multidisciplinary tumor board meetings held before and after surgery were less frequent in Iceland (92% vs. 96%) compared to Sweden (98% vs. 99%) in 2016 (p<0,01) but no difference was seen in 2017. A sentinel node surgery was done in 69% of the cases in Iceland compared to 94% in Sweden (p<0,01). For cancers ≤30mm breast conserving surgery was done in 48% cases in Iceland but 80% in Sweden (p<0,01). In Iceland 87% of the cases had radiation therapy after breast conserving surgery but 94% in Sweden (p<0,01). Among mastectomy patients with lymph node metastases, 49% received radiation therapy in Iceland compared to 83% in Sweden (p<0,01). CONCLUSION: Differences were seen in several areas of diagnosis and treatment of invasive breast cancer between Iceland and Sweden. With quality registration it will be possible to monitor and set goals for the diagnosis and treatment, with the aim of providing the best treatment to as many patients as possible.Peer reviewe

A genome-wide study of allelic imbalance in human testicular germ cell tumors using microsatellite markers

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldTesticular germ cell tumors (TGCT) arise by multistep carcinogenesis pathways involving selective losses and gains of chromosome material. To locate cancer genes underlying this selection, we performed a genome-wide study of allelic imbalance (AI) in 32 tumors, using 710 microsatellite markers. The highest prevalence of AI was found at 12p, in line with previous studies finding consistent gain of the region in TGCTs. High frequency of AI was also observed at chromosome arms 4p, 9q, 10p, 11q, 11p, 13q, 16q, 18p, and 22q. Within 39 candidate regions identified by mapping of smallest regions of overlap (SROs), the highest frequency of AI was at 12p11.21 approximately p11.22 (62%), 12p12.1 approximately p13.1 (53%), 12p13.1 approximately p13.2 (53%), 11q14.1 approximately q14.2 (53%), 11p13 approximately p14.3 (47%), 9q21.13 approximately q21.32 (47%), and 4p15.1 approximately p15.2 (44%). Two genes known to be involved in cancer reside in these regions, ETV6 at 12p13.2 (TEL oncogene) and WT1 at 11p13. We also found a significant association (P = 0.02) between AI at 10q21.1 approximately q22.2 and higher clinical stage. This study contributes to the ongoing search for genes involved in transformation of germ cells and provides a useful reference point to previous studies using cytogenetic techniques to map chromosome changes in TGCTs

ECM1 secreted by HER2-overexpressing breast cancer cells promotes formation of a vascular niche accelerating cancer cell migration and invasion.

To access publisher's full text version of this article click on the hyperlink belowThe tumor microenvironment is increasingly recognized as key player in cancer progression. Investigating heterotypic interactions between cancer cells and their microenvironment is important for understanding how specific cell types support cancer. Forming the vasculature, endothelial cells (ECs) are a prominent cell type in the microenvironment of both normal and neoplastic breast gland. Here, we sought out to analyze epithelial-endothelial cross talk in the breast using isogenic non-tumorigenic vs. tumorigenic breast epithelial cell lines and primary ECs. The cellular model used here consists of D492, a breast epithelial cell line with stem cell properties, and two isogenic D492-derived EMT cell lines, D492M and D492HER2. D492M was generated by endothelial-induced EMT and is non-tumorigenic while D492HER2 is tumorigenic, expressing the ErbB2/HER2 oncogene. To investigate cellular cross talk, we used both conditioned medium (CM) and 2D/3D co-culture systems. Secretome analysis of D492 cell lines was performed using mass spectrometry and candidate knockdown (KD), and overexpression (OE) was done using siRNA and CRISPRi/CRISPRa technology. D492HER2 directly enhances endothelial network formation and activates a molecular axis in ECs promoting D492HER2 migration and invasion, suggesting an endothelial feedback response. Secretome analysis identified extracellular matrix protein 1 (ECM1) as potential angiogenic inducer in D492HER2. Confirming its involvement, KD of ECM1 reduced the ability of D492HER2-CM to increase endothelial network formation and induce the endothelial feedback, while recombinant ECM1 (rECM1) increased both. Interestingly, NOTCH1 and NOTCH3 expression was upregulated in ECs upon treatment with D492HER2-CM or rECM1 but not by CM from D492HER2 with ECM1 KD. Blocking endothelial NOTCH signaling inhibited the increase in network formation and the ability of ECs to promote D492HER2 migration and invasion. In summary, our data demonstrate that cancer-secreted ECM1 induces a NOTCH-mediated endothelial feedback promoting cancer progression by enhancing migration and invasion. Targeting this interaction may provide a novel possibility to improve cancer treatment.Landspitali University Hospital Science Fund University of Iceland Research Fund Icelandic Science and Technology Polic