Cancer Genetics

Prostate cancer (PCa) is recognized as one of the most common malignancies that greatly affects the male population globally. Breast cancer gene 1 (BRCA1) is an important tumor suppressor gene that plays a central role in the maintenance of genomic integrity by promoting the repair of double-strand breaks of DNA. Here, we present a pilot study to examine the promoter methylation and gene expression of the BRCA1 gene in patients with PCa in Erbil governorate, Iraq. The collection of samples took place in Erbil City, Iraq, specifically at Rizgary Hospital, PAR Hospital, and Al-Mufti's private laboratory. A total of 40 tissue samples were collected from age-matched individuals, comprising 30 pathologically confirmed PCa cases and 10 normal prostatic tissue taken from individuals who, during diagnosis, were found to be negative for PCa. Data on demographic and clinical information, such as pathological stage, age, and prostate-specific antigen (PSA) level, were gathered from the medical records. The impact of the promoter methylation was forecasted using the DNA bisulfite conversion technique and methyl-specific PCR (MSP) with specific primers for the BRCA1 promoter region. The assessment of BRCA1 expression was conducted using quantitative real-time PCR (qPCR). Among the 30 patients examined, 76.6% (23 cases) were found to have BRCA1 promoter methylation, and none of the normal tissues appeared to have DNA methylation. BRCA1 promoter methylation was positively associated with the advanced stage of disease (p=0.01) and Gleason score (p=0.007). The analysis revealed a significant downregulation of the BRCA1 gene expression in methylated tumor samples as compared to non-methylated tumors and normal tissues, suggesting the role of epigenetic silencing. To the best of our knowledge, this is the first study investigating methylation status and level of BRCA1 mRNA transcripts among PCa patients in Iraq. Our findings suggest that promoter hypermethylation of the BRCA1 gene could serve as a viable biomarker for PCa, marking a significant discovery.

The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Cover Image: Immunofluorescence staining of human prostate cancer tissue engrafted into an immunecompromised mouse, showing nests of keratinized tumor cells (green), by Alan K. Meeker PhD (Johns

Cancer-a term that evokes global concern-extends beyond a single disease entity claiming 9.7 million lives with incidence of 20 million per year. Transforming Growth Factor Beta Regulator 4 (TBRG4) not only contributes to the progression of hepatocellular carcinoma (HCC), but also drives the lethal advance of lung cancer, oral squamous cell carcinoma (OSCC), breast cancer and multiple myeloma. Therefore, we aimed to systemically review the role of TBRG4 in cancer progression. MEDLINE via PubMed, Cochrane Central, Embase, and Google Scholar electronic databases were strategically searched. Upon comprehensive full-text assessment, ten articles meeting inclusion criteria were incorporated. ROBINS-E and QUIPS tools were used for quality assessment. In majority of the studies, TBRG4 expression-at both mRNA and protein levels-was elevated in tumour cells relative to adjacent normal tissues across a spectrum of cancers. Statistically significant correlations were, observed between TBRG4 expression and advanced clinical stages (III and IV) of OSCC, as well as with high histological grade (IV) and advanced tumour stages (T3 and T4) of HCC. This comprehensive systematic review elucidates that across a spectrum of malignancies, TBRG4 emerges as a compelling prognostic molecular marker intricately linked to tumour progression, poor differentiation, therapeutic resistance, and diminished survival outcomes. these insights accentuate its multifaceted potentialserving not only as a diagnostic adjunct (early lesion stratification in oral premalignant lesion such as leukoplakia), but also as a prognostic indicator (in OSCC and HCC), a predictive biomarker (for pharmacological response in Colorectal Cancer), and conceivably as a therapeutic target.

There are several theories that explain the occurrence of such a formidable disease as cancer. But is there a unifying beginning in them? Is there a single mechanism of tumor formation, and is that invisible, hidden thread found?

The new concept will try to reveal these relationships and explain the possible mechanism of the formation of malignant neoplasms.

234 diagnostic formalin-fixed paraffin-embedded (FFPE) blocks from homogeneously treated patients with locally advanced head and neck squamous cell carcinoma (HNSCC) within a multicentre phase III clinical trial were characterised. The mutational spectrum was examined by next generation sequencing in the 26 most frequent oncogenic drivers in cancer and correlated with treatment response and survival. Human papillomavirus (HPV) status was measured by p16INK4a immunohistochemistry in oropharyngeal tumours. Clinicopathological features and response to treatment were measured and compared with the sequencing results. The results indicated TP53 as the most mutated gene in locally advanced HNSCC. HPV-positive oropharyngeal tumours were less mutated than HPV-negative tumours in TP53 (p < 0.01). Mutational and HPV status influences patient survival, being mutated or HPV-negative tumours associated with poor overall survival (p < 0.05). No association was found between mutations and cl...

CDKN1B , a cyclin-dependent kinase inhibitor associated with G1 arrest, was recently proposed as an important tumor suppressor gene in small bowel neuroendocrine tumors (SBNETs). The rate of frameshift mutations in SBNET primaries are reportedly 7.4%, and hemizygous deletions are 6.7%. We set out to confirm the role of CDKN1B mutations and copy number variants (CNVs) in primary SBNETs, and whether these are also found in pancreatic neuroendocrine tumors (PNETs). Genomic DNA was isolated from 90 primary SBNETs and 67 PNETs. Coding exons of CDKN1B were amplified by PCR and sequenced. CNV analysis was performed by quantitative PCR, p27 expression was evaluated using immunohistochemistry. In SBNETS, three frameshifts, one missense mutation, and three CNVs were observed. The total rate of CDKN1B alterations was 7.0% (6 of 86; 95% confidence interval (CI) 3.2-4.4%). The frameshift rate was 3.5% (95% CI 1.1-9.8%). One SBNET patient had a hemizygous deletion of CDKN1B, and two patients had duplications (3.4%; 95% CI -0.41-7.2%). One PNET patient had a duplication, and two patients had hemizygous deletions (4.8%; 95% CI -0.44-10%). Alterations of cell-cycle control due to alterations in CDKN1B may be one mechanism by which SBNETs develop, which could have implications for new treatment modalities.

Background: Ollier disease is a rare, non-hereditary disorder which is characterized by the presence of multiple enchondromas (ECs), benign cartilaginous neoplasms arising within the medulla of the bone, with an asymmetric distribution. The risk of malignant transformation towards central chondrosarcoma (CS) is increased up to 35%. The aetiology of Ollier disease is unknown. Methods: We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis using Affymetrix SNP 6.0 array on 37 tumours of 28 Ollier patients in combination with expression array using Illumina BeadArray v3.0 for 7 ECs of 6 patients. Results: Non-recurrent EC specific copy number alterations were found at FAM86D, PRKG1 and ANKS1B. LOH with copy number loss of chromosome 6 was found in two ECs from two unrelated Ollier patients. One of these patients also had LOH at chromosome 3. However, no common genomic alterations were found for all ECs. Using an integration approach of SNP and expression array we identified loss as well as down regulation of POU5F1 and gain as well as up regulation of NIPBL. None of these candidate regions were affected in more than two Ollier patients suggesting these changes to be random secondary events in EC development. An increased number of genetic alterations and LOH were found in Ollier CS which mainly involves chromosomes 9p, 6q, 5q and 3p. We present the first genome-wide analysis of the largest international series of Ollier ECs and CS reported so far and demonstrate that copy number alterations and LOH are rare and non-recurrent in Ollier ECs while secondary CS are genetically unstable. One could predict that instead small deletions, point mutations or epigenetic mechanisms play a role in the origin of ECs of Ollier disease.

BackgroundOllier disease is a rare, non-hereditary disorder which is characterized by the presence of multiple enchondromas (ECs), benign cartilaginous neoplasms arising within the medulla of the bone, with an asymmetric distribution. The risk of malignant transformation towards central chondrosarcoma (CS) is increased up to 35%. The aetiology of Ollier disease is unknown.MethodsWe undertook genome-wide copy number and loss of heterozygosity (LOH) analysis using Affymetrix SNP 6.0 array on 37 tumours of 28 Ollier patients in combination with expression array using Illumina BeadArray v3.0 for 7 ECs of 6 patients.ResultsNon-recurrent EC specific copy number alterations were found at FAM86D, PRKG1 and ANKS1B. LOH with copy number loss of chromosome 6 was found in two ECs from two unrelated Ollier patients. One of these patients also had LOH at chromosome 3. However, no common genomic alterations were found for all ECs. Using an integration approach of SNP and expression array we identi...

Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilagin...

Background: Ollier disease is a rare, non-hereditary disorder which is characterized by the presence of multiple enchondromas (ECs), benign cartilaginous neoplasms arising within the medulla of the bone, with an asymmetric distribution. The risk of malignant transformation towards central chondrosarcoma (CS) is increased up to 35%. The aetiology of Ollier disease is unknown. Methods: We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis using Affymetrix SNP 6.0 array on 37 tumours of 28 Ollier patients in combination with expression array using Illumina BeadArray v3.0 for 7 ECs of 6 patients. Results: Non-recurrent EC specific copy number alterations were found at FAM86D, PRKG1 and ANKS1B. LOH with copy number loss of chromosome 6 was found in two ECs from two unrelated Ollier patients. One of these patients also had LOH at chromosome 3. However, no common genomic alterations were found for all ECs. Using an integration approach of SNP and expression array we identified loss as well as down regulation of POU5F1 and gain as well as up regulation of NIPBL. None of these candidate regions were affected in more than two Ollier patients suggesting these changes to be random secondary events in EC development. An increased number of genetic alterations and LOH were found in Ollier CS which mainly involves chromosomes 9p, 6q, 5q and 3p. We present the first genome-wide analysis of the largest international series of Ollier ECs and CS reported so far and demonstrate that copy number alterations and LOH are rare and non-recurrent in Ollier ECs while secondary CS are genetically unstable. One could predict that instead small deletions, point mutations or epigenetic mechanisms play a role in the origin of ECs of Ollier disease.

MNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix–loop–helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and REL, the oncogenic member of the NF-κB family. REL participates in important biological processes and it is altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB p...

This paper proposes a mechanistic cascade model for cancer initiation grounded in a biophysical mismatch: high atomic density minerals that exceed the cellular decomposition capacity within a metabolically acceptable timeframe trigger a workload distribution response-cell division. When the division cascade becomes self-sustaining and the local nutrient supply fails to match the expanding cell population, the system transitions into the pathological state recognized as cancer. Evidence from six independent research fieldsmicrobiology, molecular cell biology, cellular biology, heavy metal toxicology, animal model research, and tumor microenvironment research-independently corroborates each phase of this cascade. Animal model experiments on mice and rats directly confirm the proposed molecular pathway: high atomic density mineral load disrupts mitochondrial oxidative phosphorylation, triggers ERK pathway activation, causes metabolic reprogramming, and results in uncontrolled cell proliferation. The model provides a unified upstream explanation for the Warburg effect, tumor microenvironment acidification, immune non-response to selfcells, and the presence of differentiated structures within certain tumors.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a coun...

Figure 1a After galanin is released, the neuropeptide enhances the individual's desire to consume additional foods with high fat, Appendix Risk factors for vulvovaginal candidiasis are numerous; amongst them include pregnancy, poorly controlled diabetes, Using oral ADITUM Journal of Oncology and Cancer Screening

We previously reported that the intronic tagSNP +357G/C in the metastasis suppressor HTPAP is associated with metastasis and prognosis of hepatocellular carcinoma (HCC). The aim of this study was to investigate whether SNPs in the HTPAP promoter modulate HTPAP expression and prognosis of HCC. Genomic DNA from 572 microdissected HCCs were genotyped by pyrosequencing and verified by direct sequencing. Haplotype blocks were analyzed. Reporter plasmids were constructed and transfected into HCC cell lines. Transcriptional activities of plasmids were analyzed by dual-luciferase reporter systems. HTPAP expression was measured by real-time quantitative PCR, western blots, and tissue microarrays. Invasion was assessed by Matrigel assays. The prognostic values of HTPAP promoter SNPs in HCC were evaluated by Kaplan-Meier and Cox regression analyses. We identified six SNPs, including -1053A/G and +64G/C, in the HTPAP promoter. The SNPs were in complete linkage disequilibrium, resulting in three promoter haplotypes (promoter I:-1053AA/+64GG, promoter II: -1053AG/+64GC, and promoter III: -1053GG/+64CC). Promoter I manifested the highest luciferase index (p,0.005). However, no significant difference was observed between promoters II and III. We consistently found that HTPAP mRNA and protein levels were significantly higher in promoter I than that of promoter II+III (p,0.001). Invasion was increased in HCC cells transfected with promoters II+III compared to those transfected with promoter I (p,0.05). The HTPAP promoter II+III haplotype was associated with significantly increased metastasis compared to that of promoter I (p = 0.023). The postoperative five-year overall survival of patients with promoters II+III was lower than that of patients with promoter I (p = 0.006). Multivariate analysis showed that the promoter II+III haplotype was an adverse prognostic marker in HCC. The genetic variants at loci -1053 and +64 of the HTPAP promoter affect the expression of HTPAP, which might be a novel determinant and target for HCC prognosis.

Histology of malignant glioma depicts dense proliferative areas rich in angiogenesis as well as dissemination of neoplastic cells into adjacent brain tissue. Although the mechanisms that trigger transition from proliferative to invasive phenotypes are complex, the dichotomy of cell proliferation and migration, the ''Go or Grow'' hypothesis, argues for specific and coordinated regulation of these phenotypes. We investigated transcriptional elements that accompany the phenotypes of migration and proliferation, and consider the therapeutic significance of the ''Go or Grow'' hypothesis. Interrogation of matched core and rim regions from human glioblastoma biopsy specimens in situ (n = 44) revealed higher proliferation (Ki67 labeling index) in cells residing at the core compared to the rim. Profiling activated transcription factors in a panel of migration-activated versus migration-restricted GBM cells portrayed strong NF-kB activity in the migratory cell population. In contrast, increased c-Myc activity was found in migration-restricted proliferative cells. Validation of transcriptional activity by NF-kB-or c-Myc-driven GFP or RFP, respectively, showed an increased NF-kB activity in the active migrating cells, whereas the proliferative, migration restricted cells displayed increased c-Myc activity. Immunohistochemistry on clinical specimens validated a robust phosphorylated c-Myc staining in tumor cells at the core, whereas increased phosphorylated NF-kB staining was detected in the invasive tumor cells at the rim. Functional genomics revealed that depletion of c-Myc expression by siRNA oligonucleotides reduced cell proliferation in vitro, but surprisingly, cell migration was enhanced significantly. Conversely, inhibition of NF-kB by pharmacological inhibitors, SN50 or BAY-11, decreased both cell migration in vitro and invasion ex vivo. Notably, inhibition of NF-kB was found to have no effect on the proliferation rate of glioma cells. These findings suggest that the reciprocal and coordinated suppression/activation of transcription factors, such as c-Myc and NF-kB may underlie the shift of glioma cells from a ''growing-to-going'' phenotype.

PeutzeJeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotypeephenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER +ve ) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.

Recent tumor genome sequencing confirmed that one tumor often consists of multiple cell subpopulations (clones) which bear different, but related, genetic profiles such as mutation and copy number variation profiles. Thus far, one tumor has been viewed as a whole entity in cancer functional studies. With the advances of genome sequencing and computational analysis, we are able to quantify and computationally dissect clones from tumors, and then conduct clone-based analysis. Emerging technologies such as single-cell genome sequencing and RNA-Seq could profile tumor clones. Thus, we should reconsider how to conduct cancer systems biology studies in the genome sequencing era. We will outline new directions for conducting cancer systems biology by considering that genome sequencing technology can be used for dissecting, quantifying and genetically characterizing clones from tumors. Topics discussed in Part 1 of this review include computationally quantifying of tumor subpopulations; clone-based network modeling, cancer hallmark-based networks and their high-order rewiring principles and the principles of cell survival networks of fast-growing clones.

Individual cancer cells carry a bewildering number of distinct genomic alterations (e.g., copy number variations and mutations), making it a challenge to uncover genomic-driven mechanisms governing tumorigenesis. Here, we performed exome sequencing on several breast cancer cell lines that represent two subtypes, luminal and basal. We integrated these sequencing data and functional RNAi screening data (for the identification of genes that are essential for cell proliferation and survival) onto a human signaling network. Two subtype-specific networks that potentially represent core-signaling mechanisms underlying tumorigenesis were identified. Within both networks, we found that genes were differentially affected in different cell lines; i.e., in some cell lines a gene was identified through RNAi screening, whereas in others it was genomically altered. Interestingly, we found that highly connected network genes could be used to correctly classify breast tumors into subtypes on the bas...

Previous studies have shown frequent allelic losses of chromosomes 9p, 10, 17p, and 22q in glial tumors. Other researchers have briefly reported that glial tumors may also show allelic losses of chromosome 19, suggesting a putative tumor suppressor gene locus on this chromo some (D. T. Ransom et al., Proc. Am. Assoc. Cancer Res., 32: 302, 1991). To evaluate whether loss of chromosome 19 alÃ-elesis common in glial tumors of different types and grades, we performed Southern blot restriction fragment length polymorphism analysis for multiple chro mosome 19 loci in 122 gliomas from 116 patients. Twenty-nine tumors had loss of constitutional heterozygosity of 19q, and four tumors had partial deletions of 19q. Allelic losses on 19q were restricted to grade III anaplastic astrocytomas (4/9) and grade IV glioblastomas (11/46), grade II Oligodendrogliomas (2/5) and grade III anaplastic oligodendrogliomas (2/2), and grade II (5/8) and grade III (5/7) mixed oligoastrocytomas. These data demonstrate genetic similarities between astrocytomas, Oligodendrogliomas, and mixed glial tumors and indicate the presence of a glial tumor suppressor gene on chromosome 19q.

TEL-AML1 (ETV6-RUNX1) fusion gene which is formed prenatally in 1% of the newborns, is a common genetic abnormality in childhood Bcell precursor acute lymphoblastic leukemia. But only one child out of a hundred children born with this fusion gene develops leukemia (bottleneck phenomenon) later in its life, if contracts the second mutation. In other words, out of a hundred children born with TEL-AML1 only one child is at risk for leukemia development, which means that TEL-AML1 fusion gene is not sufficient for overt leukemia. There is a stringent requirement for a second genetic abnormality for leukemia development and this is the real or the ultimate cause of the leukemia <em>bottleneck</em> phenomenon. In most cases of TEL-AML1<sup>+</sup> leukemia, the translocation t(12;21) is complemented with the loss of the normal TEL gene, not involved in the translocation, on the contralateral 12p. The loss of the normal TEL gene,…

Advances in technology within biomedical sciences have led to an inundation of data across many fields, raising new challenges in how best to integrate and analyze these resources. For example, rapid chemical screening programs like the US Environmental Protection Agency's ToxCast and the collaborative effort, Tox21, have produced massive amounts of information on putative chemical mechanisms where assay targets are identified as genes; however, systematically linking these hypothesized mechanisms with in vivo toxicity endpoints like disease outcomes remains problematic. Herein we present a novel use of normalized pointwise mutual information (NPMI) to mine biomedical literature for gene associations with biological concepts as represented by Medical Subject Headings (MeSH terms) in PubMed. Resources that tag genes to articles were integrated, then cross-species orthologs were identified using UniRef50 clusters. MeSH term frequency was normalized to reflect the MeSH tree structu...

amplifications (CNA), single nucleotide variants (SNV), and insertion-deletions (indel) were identified. Results: ERBB2 alterations were detected in 50 patients (10.8%). ERBB2 SNV, CNA, and indel were found in 27 (5.8%), 25 (5.4%), and 9 (1.9%) patients, respectively. ERBB2 amplification was most frequently identified in gastric (20%; 5/25), colorectal (9.3%; 4/43), lung (4%; 9/226), and breast (3.2%; 1/31) cancer patients. It was often mutually exclusive with other oncogenic drivers in gastric (80%; 4/5) and colorectal (50%; 2/4) but not in other cancers, where concurrent activating BRAF, RAS, and EGFR mutations were observed. Mean ERBB2 CN was also higher in gastric and colorectal cancers compared to others (14.3 vs 3.5, respectively). Interestingly, one gastric cancer patient, whose ERBB2 CNA was identified after progression on 4 prior therapies, demonstrated disease stabilization upon initiation of trastuzumab/FOLFOX. Conclusions: Our data indicate that ERBB2 amplification is a common event in several solid tumor types among East Asian cancer patients. In particular, higher ERBB2 incidence and CN were observed in gastric and colorectal cancer patients in the absence of other oncogenic alterations, underscoring its likely role as the driver in those settings. Finally, we show the potential of comprehensive cfDNA testing in identifying patients who may benefit from HER2-targeted therapies.

The genetics involved in Ewing sarcoma susceptibility and prognosis are poorly understood. EWS/FLI and related EWS/ETS chimeras upregulate numerous gene targets via promoter-based GGAA-microsatellite response elements. These microsatellites are highly polymorphic in humans, and preliminary evidence suggests EWS/FLI-mediated gene expression is highly dependent on the number of GGAA motifs within the microsatellite. Objectives: Here we sought to examine the polymorphic spectrum of a GGAA-microsatellite within the NR0B1 promoter (a critical EWS/FLI target) in primary Ewing sarcoma tumors, and characterize how this polymorphism influences gene expression and clinical outcomes. Results: A complex, bimodal pattern of EWS/FLI-mediated gene expression was observed across a wide range of GGAA motifs, with maximal expression observed in constructs containing 20-26 GGAA motifs. Relative to white European and African controls, the NR0B1 GGAA-microsatellite in tumor cells demonstrated a strong bias for haplotypes containing 21-25 GGAA motifs suggesting a relationship between microsatellite function and disease susceptibility. This selection bias was not a product of microsatellite instability in tumor samples, nor was there a correlation between NR0B1 GGAA-microsatellite polymorphisms and survival outcomes. Conclusions: These data suggest that GGAA-microsatellite polymorphisms observed in human populations modulate EWS/ FLI-mediated gene expression and may influence disease susceptibility in Ewing sarcoma.

legend N2D N1D 2LPEG N2D vs. 2LPEG N1D vs. 2LPEG EFFICACY Primary analysis set, n1⁄4 275 Primary analysis set, n1⁄4 275 Primary analysis set, n1⁄4 272 Primary endpoint: Patients with successful overall bowel cleansing efficacy (HCS) [n] 253 (92.0%) 245 (89.1%) 238 (87.5%) -4.00%* [0.055] -6.91%* [0.328] Supportive secondary endpoint: Patients with successful overall bowel cleansing efficacy (BBPS) [n] 249 (90.5%) 243 (88.4%) 232 (85.3%) n.a. n.a. Primary endpoint: Excellent plus Good cleansing rate in colon ascendens (primary analysis set) [n] 87 (31.6%) 93 (33.8%) 41 (15.1%) 8.11%* [50.001] 10.32%* [50.001] Key secondary endpoint: Adenoma detection rate, colon ascendens 11.6% 11.6% 8.1% -4.80%; 12.00%** [0.106] -4.80%; 12.00%** [0.106] Key secondary endpoint: Adenoma detection rate, overall colon 26.6% 27.6% 26.8% -8.47%; 8.02%** [0.569] -7.65%; 9.11%** [0.455] Key secondary endpoint: Polyp detection rate, colon ascendens 23.3% 18.6% 16.2% -1.41%; 15.47%** [0.024] -6.12%; 10.82%** ...

Our previous comparative genomic hybridization (CGH) study of Ewing sarcoma and related tumors showed that DNA sequence copy number increases of 1q21 ‫ف‬ q22 and of chromosomes 8 and 12 were associated with trends toward poor survival (Armengol et al., Br J Cancer 1997, 75, 1403-1409). These trends were not statistically significant. In the present study, we analyzed 28 primary Ewing sarcomas and related tumors by CGH to study whether these (or other) changes have prognostic value in these tumors. Twenty-one tumors (75%) had changes with a mean of 1.9 changes per tumor. The most frequent aberration was gain of chromosome 8 in 10 tumors (36%). Five tumors (18%) had copy number increases at 1q21 ‫ف‬ 22 and 5 had gain of 7q. Copy number increase of 6p21.1 ‫ف‬ pter, gain of chromosome 12, and loss of 16q were seen in 11%. Copy number increases of 1q21 ‫ف‬ q22 and of chromosomes 8 and 12 were associated with trends toward worse outcome, but the differences did not reach statistical significance. A novel finding is the association of copy number increase at 6p with worse distant disease-free ( P ϭ 0.04) and overall survival ( P ϭ 0.004). To confirm this finding and to see whether copy number increases of 1q21 ‫ف‬ q22 and of chromosomes 8 and 12 have definite prognostic value, a larger number of cases needs to be studied.

Background: Unicystic ameloblastoma (UA) is an odontogenic tumor known for its complex histopathological features and high recurrence rates. Accurate prediction of recurrence is essential for guiding appropriate treatment and improving patient outcomes. Objective: This study aims to develop and evaluate a deep-learning model for predicting UA recurrence using Hematoxylin and Eosin (H&E) stained whole-slide images (WSIs). Methods: A retrospective analysis was conducted using annotated histopathological slides of UA. The dataset was enhanced through advanced image augmentation techniques. A novel deep-learning architecture, ResCRAMNet, was employed to analyze WSIs. Model performance was benchmarked against traditional approaches. Results: The proposed ResCRAMNet model demonstrated superior performance, achieving a prediction accuracy of 92 %, outperforming conventional methods. Conclusion: This study confirms the effectiveness of deep-learning models in histopathology and introduces a robust framework for predicting UA recurrence. The findings contribute to the advancement of precision diagnostics in oral pathology. The ResCRAMNet model can be seamlessly integrated into clinical workflows as a decision-support tool, rapidly analyzing digitized H&E slides to identify high-risk UA cases. This enables personalized treatment planning and improved patient monitoring, ultimately enhancing clinical outcomes and optimizing healthcare resources.

Acute promyelocytic leukemia (APL) with the unique t(15;17) translocation has a high complete remission and disease-free survival rates following chemotherapy with all-trans-retinoic acid. Chemotherapy complications including secondary malignancies are rare. In this report we present therapy-related T-lymphoblastic lymphoma following APL treatment. The bone marrow analysis showed MLL and MAML2 genes rearrangement that can explain the molecular basis for the lymphoma development.

Recent years have seen development and implementation of anticancer therapies targeted to particular gene mutations, but methods to assay clinical cancer specimens in a comprehensive way for the critical mutations remain underdeveloped. We have developed UW-OncoPlex, a clinical molecular diagnostic assay to provide simultaneous deep-sequencing information, based on >500× average coverage, for all classes of mutations in 194 clinically relevant genes. To validate UW-OncoPlex, we tested 98 previously characterized clinical tumor specimens from 10 different cancer types, including 41 formalin-fixed paraffin-embedded tissue samples. Mixing studies indicated reliable mutation detection in samples with ≥ 10% tumor cells. In clinical samples with ≥ 10% tumor cells, UW-OncoPlex correctly identified 129 of 130 known mutations [sensitivity 99.2%, (95% CI, 95.8%-99.9%)], including single nucleotide variants, small insertions and deletions, internal tandem duplications, gene copy number gain...

Breast cancer (BC) is the most common neoplasia in women, and it can be caused by mutations in high penetrance genes (BRCA1 and BRCA2), characterizing the Hereditary Breast and Ovarian Cancer (HBOC) Syndrome. However, genes with moderate penetrance also contribute for the development of cancer, such as ATM, with a relative risk of 2.3 for the development of BC. ATM is compound by 62 exons translated, coding a protein involved in monitoring and DNA repair of double-strand breaks. Considering the difficulty of sequencing the whole gene due to its size, this study aims to search hotspots regions in ATM, estimating the prevalence of pathogenic variants and elucidating the significance of variants of uncertain significance (VUS) in silico. Hotspot regions were identified through literature review and cases with complete ATM sequencing. Unrelated subjects with HBOC clinical criteria were selected after sign informed consent. Genomic DNA was obtained from peripheral blood and exons 26, 37,...

Cervical cancer frequently associated with multiple HPV types. Recent report suggests that a polymorphism of thep53 tumor suppressor gene that results in the substitution of a proline residue with an arginine at position 72 protein,it act as a risk factor in HPV associated malignancies. The present study, we examined the genotypic frequency ofthis polymorphisms in 24 patients with cervical cancer using allele-specific polymerase chain reaction to detectedP53 polymorphism at 72 codon. The frequency distribution of genotypes in cervical cancer patients as 29%(7tumors) for the arginine/arginine allele, 63% (15 tumors) for the heterozygous arginine/proline status, and 8% (2tumors) for the proline/proline allele respectively. Allele frequencies of proline and arginine at 72 codon of P53gene in proline (0.400) and arginine (0.600) in cervcal cancer patients. Statistically significant difference wasobserved between the Proline/proline, arginine/arginine and proline/arginine genotypes in ce...

Bizarre parosteal osteochondromatous proliferation (BPOP), also known as Nora's lesion is a rare osteocartilaginous lesion composed of a disorganized mixture of cartilage, bone, and fibrous tissue. In this article we report a case of BPOP arising on the proximal and middle phalanx of ring finger in a 31 year-old woman. The clinical, radiographic, MR imaging and histopathologic findings of it are described .The symptoms regressed spontaneously in 2 month after incisional biopsy.

Background: Myxofibrosarcoma comprises a spectrum of malignant neoplasms withprominent myxoid stromata, cellular pleomorphism, and distinct curvilinear vascular patterns. These neoplasms mainly affect patients in the sixth to eighth decades of life and the overall 5-year survival rate is 60-70%. Methods: After the establishment of the novel myxofibrosarcoma cell lines MUG-Myx1, cells were characterized using short tandem repeat (STR), copy number variation (CNV), and genotype/loss-of-heterozygosity (LOH) analyses. The growth behaviour of the cells was analyzed with the xCELLigence system and an MTS assay. The tumourigenicity of MUG-Myx1 was proved in NOD/SCID mice. Additionally, a stem-like cell population with high enzymatic activity of aldehyde dehydrogenase 1 (ALDH1 high ) was isolated for the first time from myxofibrosarcoma cells using the Aldefluor® assay followed by FACS analysis. The frozen primary parental tumour tissue and the MUG-Myx1 cell line showed the same STR profile at the markers D3S1358,

6 Hozyasz KK. Unrecognised coeliac disease in mother as a risk factor for neural tube defect, cleft lip and/or cleft palate in oVspring (in Polish). Doctoral thesis. Warsaw: National Research Institute of Mother and Child, 2000. 7 Czeizel AE. Folic acid and prevention of neural tube defects.