A new prognostic factor of breast cancer: High carboxyl ester lipase expression related to poor survival Publication date: November 2019 Source: Cancer Genetics, Volume 239 Author(s): Yingnan Cui, Yan Jiao, Keren Wang, Miao He, Zhaoying Yang Abstract Objective The enzyme carboxyl ester lipase (CEL), known as bile salt-dependent lipase (BSDL) or bile salt-stimulated lipase (BSSL), is mainly expressed in pancreatic acinar cells and lactating mammary glands. To investigate the link between CEL expression of breast cancer (BC) tissues and the survival of BC patients by analyzing The Cancer Genome Atlas Breast Carcinoma (TCGA-BRCA) level 3 data. Methods The clinical information and RNA-sequencing (RNA-Seq) expression data were downloaded from TCGA. Patients were divided into a high CEL expression group and a low CEL expression group using the optimal cutoff value (5.611) identified from the ROC curve. Chi-square test and Fisher exact test were used to find the correlation between the expression of CEL and clinicopathologic features. To assess the diagnostic capability, the receiver operating characteristic (ROC) curve of CEL was drawn. The survival differences between high and low CEL expression groups were compared by Cox regression analysis. Log-rank test was applied to the calculation of p values and the comparison of the Kaplan–Meier curves. Furthermore, Gene Expression Omnibus (GEO) datasets were used for external data validation. Results Analysis of 1104 cases of tumor data showed that CEL was over-expressed in breast cancer. There were relationships between high CEL expression and clinicopathologic features. The high CEL expression group had a lower survival. By analyzing the area under the ROC curve (AUC) of CEL, it was found to have a limited diagnostic capability. CEL expression may be an independent prognostic factor for breast cancer survival through the multivariate analysis. The validation in GEO datasets also showed that CEL expression was higher in breast tumor tissues than in normal breast tissues. High CEL expression was associated with the poor overall survival of breast cancer. Conclusions High CEL expression may be an independent prognostic factor for the poor survival of breast cancer.

Dysregulated expression of repetitive DNA in ER+/HER2- breast cancer Publication date: November 2019 Source: Cancer Genetics, Volume 239 Author(s): Cihangir Yandım, Gökhan Karakülah Abstract Limited studies on breast cancer indicated pathogenic changes in the expressions of some repeat elements. A global analysis was much needed within this context to distinguish the most significant repeats from more than a thousand repeat motifs. Utilising a previously presented RNA-seq dataset, we studied expression changes of all repeats in ER+/HER2- human breast tumour samples obtained from 22 patients in comparison to matched normal tissues. Fifty six (56) repeat subtypes including satellites and transposons were found to be differentially expressed and most of them were novel for breast cancer. HERVKC4-int and HERV1_LTRc, whose expressions correlated well with that of the estrogen receptor gene ESR1, were upregulated at the highest level. REP522 and D20S16 satellites were also significantly upregulated along with insignificant increases in the expressions of other satellites including HSATI and BSR/beta. Interestingly, expressions of REP522 and D20S16 correlated with many key breast cancer pathway (e.g. BRCA1, BRCA2, AKT1, MTOR, KRAS) and survival genes; possibly highlighting their importance in the carcinogenesis of breast. Additional differentially expressed elements such as L1P and various MER transposons also exhibited a similar pattern. Finally, our repeat enrichment analysis on the promoters of differentially expressed genes revealed further links between additional repeats and nearby genes.

Burkitt-like lymphoma in a pediatric patient with familial adenomatous polyposis Publication date: November 2019 Source: Cancer Genetics, Volume 239 Author(s): Katie M. Strobel, Jacquelyn N. Crane, Kathryn L. Bradford, Yalda Naeini, William A. May, Vivian Y. Chang Abstract Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes to multiple malignancies, most commonly colorectal carcinoma, but has rarely been associated with lymphoma. We discuss one patient found to have Burkitt-like Lymphoma (BLL) with 11q aberration in the setting of previously undiagnosed FAP. We review the literature of FAP and associated malignancies and the provisional WHO classification of Burkitt-like lymphoma with 11q aberration. Both FAP and Burkitt-like lymphoma with 11q aberration involve perturbation of the MYC network and this may provide insight into a connection between these two diagnoses. However, further study is needed to elucidate if there is an increased risk of BLL and other subtypes of lymphoma among patients with FAP in order to provide optimal counseling and surveillance for patients with FAP.

A novel BRCA1 germline mutation promotes triple-negative breast cancer cells progression and enhances sensitivity to DNA damage agents Publication date: November 2019 Source: Cancer Genetics, Volume 239 Author(s): Kun Xu, Yaqin Shi, Xin Wang, Yajuan Chen, Lin Tang, Xiaoxiang Guan Abstract Breast cancer is the most frequent malignancy and the second leading cause of cancer death in female worldwide. Compared with general population, patients with mutations in BRCA1 and BRCA2 genes confer approximately 10-fold increased risk of breast cancer. In this study, we conducted whole-exome sequencing to identify the disease-associated genes in a specific pedigree, in which at least eight individuals were diagnosed with cancers, including breast cancer, urothelial cancer, uterine cancer and colorectal cancer. Furthermore, a nonsense mutation BRCA1 p.Trp372X was identified in the proband. The Sanger sequencing data has validated the same nonsense mutation in other 4 cancer patients and 3 normal family members. Additionally, functional experiments detected that this mutation was implicated in TNBC progression, manifesting as increased cell proliferation and migration. Cells with this mutation displayed impaired recruitment of RAD51 foci and unrepaired DNA damage, potentiating drug sensitivity to PARP inhibitor and cisplatin, both in the settings of combination use or monotherapy. On the basis of its occurrence in hereditary breast cancer and its identification in pedigree, as well as its function as a disruption of BRCA1, this mutation is critical to breast cancer predisposition and progression. Patients carrying this mutation may benefit from DNA damaging treatment regimens. Conclusively, we firstly reported this nonsense mutation in family pedigree and validated its pathogenicity through in vitro functional experiments.

Rapid detection of chromosomal translocation and precise breakpoint characterization in acute myeloid leukemia by nanopore long-read sequencing Publication date: November 2019 Source: Cancer Genetics, Volume 239 Author(s): Chun Hang Au, Dona N. Ho, Beca B.K. Ip, Thomas S.K. Wan, Margaret H.L. Ng, Edmond K.W. Chiu, Tsun Leung Chan, Edmond S.K. Ma Abstract Detection of chromosomal translocation is a key component in diagnosis and management of acute myeloid leukemia (AML). Targeted RNA next-generation sequencing (NGS) is emerging as a powerful and clinically practical tool, but it depends on expression of RNA transcript from the underlying DNA translocation. Here, we show the clinical utility of nanopore long-read sequencing in rapidly detecting DNA translocation with exact breakpoints. In a newly diagnosed patient with AML, conventional karyotyping showed translocation t(10;12)(q22;p13) but RNA NGS detected NUP98-NSD1 fusion transcripts from a known cryptic translocation t(5;11)(q35;p15). Rapid PCR-free nanopore whole-genome sequencing yielded a 26,194 bp sequencing read and revealed the t(10;12) breakpoint to be DUSP13 and GRIN2B in head-to-head configuration. This translocation was then classified as a passenger structural variant. The sequencing also yielded a 20,709 bp sequencing read and revealed the t(5;11) breakpoint of the driver NUP98-NSD1 fusion. The identified DNA breakpoints also served as markers for molecular monitoring, in addition to fusion transcript expression by digital PCR and sequence mutations by NGS. We illustrate that third-generation nanopore sequencing is a simple and low-cost workflow for DNA translocation detection.

Potential of epigenetic events in human thyroid cancer Publication date: November 2019 Source: Cancer Genetics, Volume 239 Author(s): Abdelkareem A. Ahmed, Mohammed Elmujtba Adam Essa Abstract Thyroid cancer remains the highest prevailing endocrine malignancy, and its incidence rate has progressively increased in the previous years. Above 95% of thyroid tumor are follicular cells types of carcinoma in which are considered invasive type of tumor. The pathogenesis and molecular mechanism of thyroid tumors are yet remains elucidated, in spite of activating RET, RAS and BRAF carcinogenesis have been well introduced. Nemours molecular alterations have been defined and have revealed promise for their diagnostic, prognostic and therapeutic capacity but still need further confirmation. Among different types of mechanisms, the current article reviews the importance of epigenetic modifications in thyroid cancer. Increasing data from previous reports demonstrate that acquired epigenetic abnormalities together with genetic changes plays an important role in alteration of gene expression patterns. Aberrant DNA methylation has been well known in the CpG regions and profile of microRNAs (mi-RNAs) expression also involved in cancer development. In addition, the gene expression through epigenetic control contribution to thyroid cancer is analyzed and it is semi considered in the clinic. However the epigenetic of the thyroid cancer is yet remains in its early stages, and it carries encouraging potential thyroid cancer detections in its early stages, assessment of prognosis and targeted cancer treatment.

A complex and cryptic intrachromosomal rearrangement generating the FIP1L1_PDGFRA in adult acute myeloid leukemia Publication date: November 2019 Source: Cancer Genetics, Volume 239 Author(s): Nicoletta Coccaro, Luisa Anelli, Paola Orsini, Antonella Zagaria, Angela Minervini, Luciana Impera, Giuseppina Tota, Crescenzio Francesco Minervini, Cosimo Cumbo, Elisa Parciante, Maria Rosa Coserva, Immacolata Attolico, Giorgina Specchia, Francesco Albano Abstract Myeloid neoplasms with eosinophilia and abnormalities of the PDGFRA gene can benefit from therapy with tyrosine kinase inhibitors, therefore revealing the PDGFRA rearrangement is essential to ensure the best choice of treatment. The most common PDGFRA partner is the FIP1L1 gene, generating the oncoprotein FIP1L1/PDGFRA (F/P). In the majority of cases the F/P fusion gene originates from intrachromosomal rearrangement at band 4q12, and occasionally from chromosomal translocations. In both cases, the interstitial chromosomal deletion of a region involving the CHIC2 gene has been reported, which is cryptic by conventional karyotyping but detectable by Fluorescence In Situ Hybridization (FISH) analyses. Herein, we report an acute myeloid leukemia (AML) case presenting with eosinophilia; the F/P fusion gene originated from a new, cryptic and complex intrachromosomal rearrangement of 4q12. Classical FISH assay revealed abnormal hybridization signals, but the presence of the F/P chimaeric gene was demonstrated by molecular analysis. We performed molecular characterization of the chromosomal rearrangement and targeted Next-Generation Sequencing (NGS) analysis with a myeloid gene panel, revealing the presence of pathogenic genomic variants affecting the TET2 and ETV6 genes. These mutations were present as subclones at the disease onset and their clone size increased at relapse.

Confirmation of damaging effect of MSH2 c.2634+1G>C mutation on splicing, its classification and implications for counseling Publication date: November 2019 Source: Cancer Genetics, Volume 239 Author(s): Jelena Rakobradović, Ana Krivokuća, Stevo Jovandić, Vesna Kesić, Mirjana Branković-Magić Abstract Introduction Lynch syndrome (LS) is predisposing mainly to colorectal and endometrial carcinomas, but also to urinary tract cancers. LS association with upper urinary tract carcinomas is known, but its association with bladder cancer is not so clear. Confirmation of pathogenicity of detected mutations in LS-associated genes is required for adequate counseling. Material and Methods Tested young female has family history of two early colorectal and two bladder carcinomas. NGS sequencing revealed MSH2 splice site mutation c.2634+1G>C, which was confirmed by Sanger sequencing. MSH2 cDNA part containing potential splicing change was sequenced. in silico softwares were used to predict the effect of detected mutation on splicing and protein structure. ACMG Guidelines were used for mutation classification. Results in silico softwares predict damaging effect of detected mutation on splicing and loss of protein-binding domains. cDNA sequencing confirmed this mutation causes exon 15 excision. ACMG Guidelines classify this mutation as Pathogenic. Discussion MSH2 c.2634+1G>C mutation was not reported previously as LS associated. We confirmed its damaging effect on splicing. in silico tools predict consequent loss of protein domains implicating disrupted protein function. Our results suggest that this mutation should be classified as Pathogenic, and indicate inclusion of bladder cancer in LS cancer spectrum.

Single nucleotide polymorphism rs10889677 in miRNAs Let-7e and Let-7f binding site of IL23R gene is a strong colorectal cancer determinant: Report and meta-analysis Publication date: November 2019 Source: Cancer Genetics, Volume 239 Author(s): Meysam Mosallaei, Miganoosh Simonian, Emran Esmaeilzadeh, Hadi Bagheri, Maryam Miraghajani, Ahmad Reza Salehi, Valiollah Mehrzad, Rasoul Salehi Abstract Single nucleotide polymorphisms (SNPs) in the recognition sites of microRNAs (miRNAs), located at 3′ untranslated region (UTR) of mRNAs, interfere with posttranslational gene regulation. Deregulation of genes may contribute to some disease susceptibility including colorectal cancer (CRC). In the present study, in a case-control setup, 167 CRC patients and 161 control subjects were studied for allele and genotype frequency of rs10889677 polymorphism in miRNAs Let-7e and Let-7f binding sites at 3′ UTR of IL23R gene using PCR–RFLP assay. Also, related articles were retrieved from MEDLINE, Cochrane review, Google Scholar and Scopus databases for meta-analysis study. According to our results, AA genotype of SNP rs10889677 was significantly correlated with increased risk of CRC (OR = 3.10; 95% CI [1.86–5.18]; P: < 0.001). In a meta-analysis on 10 risk estimates for the CC versus AA genotype, we found an inverse association between CC SNPs and risk of all cancer (OR = 0.59; 95% CI [0.49–0.71]; P < 0.001). In conclusion, our results demonstrate that rs10889677 polymorphism is significantly associated with CRC risk.

Cytogenomic characterization of double minute heterogeneity in therapy related acute myeloid leukemia Publication date: October 2019 Source: Cancer Genetics, Volume 238 Author(s): Prasad Koduru, Weina Chen, Barbara Haley, Kevin Ho, Dwight Oliver, Kathleen Wilson Abstract Breast cancer patients treated with adjuvant chemotherapy regimens containing alkylating agents and anthracyclines are at an increased risk for secondary myeloid malignancies, either acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Complex genomic changes (karyotypes and/or gene amplification) accompany the development of the secondary neoplasms. Here we present a unique case of a breast cancer patient who developed secondary AML within 18 months of treatment with trastuzumab, pertuzumab, docetaxel, carboplatin (TCHP) and radiation. Leukemia cells had catastrophic alterations in chromosomes 8, 11, and 17. Genetic abnormalities in the leukemia cells included amplification of MYC and KMT2A as double minutes, and deletion and mutational inactivation of TP53 Concurrent amplification of different genes at different levels and on different double minutes, we have named “double minute heterogeneity.” Clinically, this case highlights the need to identify genes amplified in secondary myeloid malignancies by cytogenomic microarray (CMA) analysis since these may have therapeutic implications.