ATM whole gene deletion in an Italian family with hereditary pancreatic cancer: Challenges to cancer risk prediction associated with an 11q22.3 microdeletion Publication date: January 2020 Source: Cancer Genetics, Volume 240 Author(s): Heleen H. Arts, Lorrie Lynch, Daria Grafodatskaya, Barry Eng, Lesley Malloy, John Duck, Robyn White, Crystal Woodside, Kathleen Bell, Kevin M. Zbuk, Elizabeth McCready Abstract Hereditary pancreatic cancer has been attributed to variants of several cancer predisposition genes including ATM. While heterozygous pathogenic variants in the ATM gene are implicated as a cause of familial breast and pancreatic cancers to our knowledge ATM whole gene deletions have not been previously reported. We describe a contiguous gene deletion of the ATM locus in a multi-generation family of Italian descent with a strong family history of pancreatic cancer. A deletion of one copy of the entire ATM gene was identified by routine panel testing and further characterized by chromosomal microarray analysis. An 11q22.3 microdeletion of approximately 960 kb was identified that is predicted to result in loss of 10 genes including ATM. The deletion was identified in two additional family members including a presymptomatic daughter and an affected sibling. A normal disomic complement of the 11q22.3 region was detected in a third family member with a history of prostate and pancreatic cancer. Additional family members were not available for testing. Given available evidence that ATM haploinsufficiency can increase cancer risk, we predict that the observed copy number loss has likely contributed to hereditary cancer in this family. However, absence of the familial microdeletion in at least one affected family member suggests that ATM deletions are unlikely the sole contributing factor influencing tumor development in affected individuals. This case highlights 11q22.3 microdeletions of the ATM gene region as a possible risk factor for hereditary cancer, including pancreatic cancer. The same case provides a further cautionary tale for over interpretation of cancer risk associated tumor suppressor microdeletions and suggests that the variant may not be sufficient for tumor development or may modify the cancer risks associated with other, yet unidentified hereditary cancer genes.

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.

Transcriptomics-based screening of molecular signatures associated with patients overall survival and their key regulators in subtypes of breast cancer Publication date: November 2019 Source: Cancer Genetics, Volume 239 Author(s): Elaheh Eskandari, Jamshid Motalebzadeh Abstract Molecular subtypes of breast cancer are associated with differences in prognosis and strategies of molecular targeted therapies. Gene regulatory mechanisms as one of the reasons might modulate these differences. In the present study, we proposed a comprehensive data analysis and systems biology approach to explore molecular signatures which reduce the chance of patients overall survival and the possible mechanisms of their regulation by transcription factors (TFs) and microRNAs (miRNAs) in the main subtypes of breast tumor consist of Basal like, Her2 enriched, Luminal A and Luminal B breast cancer. In this regards, we used available microarray datasets to assess common differentially expressed genes (DEGs) in breast cancer subtypes. Using Kaplan-Meier curve analysis we identified common DEGs which are associated with decreasing in the overall survival of breast cancer patients. Furthermore, gene regulatory networks (GRNs) were depicted based on TFs and miRNAs with interest target genes. Then GRNs were analyzed and using five algorithms (Control centrality, Betweenness, Degree, Classification, and MCDS) the key regulators were identified for each subtype. In this study, we highlighted mechanisms underlying the regulation of breast cancer molecular signatures by TFs and miRNAs which their alteration reduce the chance of survival rate in each subtype of breast cancer. Our current study in a holistic insight revealed the importance of some genes and their regulators as potential prognostic markers and/or therapeutic targets in breast cancer patients.

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.

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.

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.

Progress in quantitative technique of circulating cell free DNA and its role in cancer diagnosis and prognosis Publication date: November 2019 Source: Cancer Genetics, Volume 239 Author(s): Jia-Lei Weng, Manar Atyah, Chen-Hao Zhou, Ning Ren Abstract The interest in the potential application value of circulating cell free DNA (ccfDNA) has increased rapidly in recent years, as numerous researchers have demonstrated that the change of its level in the blood is associated with many diseases. Its potential role in cancer management is of particular concern. In comparison with traditional invasive tissue biopsy, quantitative analysis of ccfDNA level for the detection of cancer is advantageous due to the non-invasiveness of blood collection. Moreover, its clinical significance in prognosis prediction and dynamic monitoring of disease progression in cancer patients is equally worthy of attention. At the same time, quantitative detection of ccfDNA is being improved to pursue higher sensitivity due to its low concentration in the blood sample. In this review, we will summarize the progress in quantitative technology of ccfDNA and describe the possible relationship between ccfDNA level and cancer diagnosis and prognosis prediction.

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.