scholarly journals A systematic screen of breast cancer patients’ exomes for retrotransposon insertions reveals disease associated genes

2020 ◽  
Author(s):  
Sylvia De Brakeleer ◽  
Jacques De Grève ◽  
Erik Teugels
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Mrna Level ◽  
Genetic Alterations ◽  
Strong Impact ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Suppressor Activity ◽  
Alu Elements ◽  
Alu Insertion

ABSTRACTBackgroundRetrotransposons are genetic elements that jump within the genome via an RNA intermediate. Although they had a strong impact on human genome evolution, only a very tiny fraction of them can be reactivated nowadays, most often with neutral or detrimental consequences. The pathological outcomes associated with such genetic alterations are poorly investigated in the clinic, merely due to their difficult detection.ResultsWe developed a strategy to detect rare retrotransposon mediated insertions in Whole Exome Sequencing data from 65 familial breast cancer patients. When restricting our search to high confidence retrotransposition events occurring in less than 10% of the samples, we identified only ten different Alu elements, two L1 elements, one SVA and two processed pseudogenes. Only two of these insertions occurred within protein coding sequences and interestingly, several of the targeted genes have been previously linked to cancer, in three cases even to increased breast cancer risk (GHR, DMBT1 and NEK10). When investigating the molecular consequences of four Alu insertions at the mRNA level, we found that the element present in the 3’UTR of GHR repressed expression of the corresponding allele. oMreover, the analysis of a near exonic Alu insertion in PTPN14 (a mediator of P53 tumor suppressor activity) revealed that this gene was imprinted and that the presence of an intronic Alu element can lead to loss of imprinting.ConclusionsOur data underline the relevance of incorporating the search for uncommon retrotransposition events in Next Generation Sequencing pipelines when analyzing patients with a suspected genetic disease.

scholarly journals Genetic Alterations in Benign Breast Biopsies of Subsequent Breast Cancer Patients

2019 ◽  
Vol 6 ◽  
Author(s):  
Savas D. Soysal ◽  
Charlotte K. Y. Ng ◽  
Luigi Costa ◽  
Walter P. Weber ◽  
Viola Paradiso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Genetic Alterations ◽  
Breast Cancer Patients

scholarly journals Detection of structural variations and fusion genes in breast cancer samples using third-generation sequencing

2021 ◽  
Author(s):  
Taobo Hu ◽  
Jingjing Li ◽  
Mengping Long ◽  
Jinbo Wu ◽  
Zhen Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Genetic Alterations ◽  
Read Length ◽  
Breast Cancer Patients ◽  
Structural Variations ◽  
Transcriptomic Sequencing ◽  
Long Read ◽  
Second Generation Sequencing ◽  
Generation Sequencing

Abstract Background: Structural variations (SVs) are common genetic alterations in the human genome that could cause different phenotypes and various diseases including cancer. However, the detection of structural variations using the second-generation sequencing was limited by its short read-length which in turn restrained our understanding of structural variations. Methods: In this study, we developed a 28-gene panel for long-read sequencing and employed it to both Oxford Nanopore Technologies and Pacific Biosciences platforms. We analyzed structural variations in the 28 breast cancer-related genes through long-read genomic and transcriptomic sequencing of tumor, para-tumor and blood samples in 19 breast cancer patients. Results: Our results showed that some somatic SVs were recurring among the selected genes, though the majority of them occurred in the non-exonic region. We found evidence supporting the existence of hotspot regions for SVs, which extended our previous understanding that they exist only for single nucleotide variations. Conclusions: In conclusion, we employed long-read genomic and transcriptomic sequencing in identifying SVs from breast cancer patients and proved that this approach holds great potential in clinical application.

scholarly journals Germline variants associated with leukocyte genes predict tumor recurrence in breast cancer patients

2019 ◽  
Vol 3 (1) ◽  
Author(s):  
Jean-Sébastien Milanese ◽  
Chabane Tibiche ◽  
Jinfeng Zou ◽  
Zhigang Meng ◽  
Andre Nantel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Clinical Outcomes ◽  
Cell Function ◽  
Recurrence Score ◽  
Oncotype Dx ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Germline Variants ◽  
Gene Signatures

Abstract Germline variants such as BRCA1/2 play an important role in tumorigenesis and clinical outcomes of cancer patients. However, only a small fraction (i.e., 5–10%) of inherited variants has been associated with clinical outcomes (e.g., BRCA1/2, APC, TP53, PTEN and so on). The challenge remains in using these inherited germline variants to predict clinical outcomes of cancer patient population. In an attempt to solve this issue, we applied our recently developed algorithm, eTumorMetastasis, which constructs predictive models, on exome sequencing data to ER+ breast (n = 755) cancer patients. Gene signatures derived from the genes containing functionally germline variants significantly distinguished recurred and non-recurred patients in two ER+ breast cancer independent cohorts (n = 200 and 295, P = 1.4 × 10−3). Furthermore, we compared our results with the widely known Oncotype DX test (i.e., Oncotype DX breast cancer recurrence score) and outperformed prediction for both high- and low-risk groups. Finally, we found that recurred patients possessed a higher rate of germline variants. In addition, the inherited germline variants from these gene signatures were predominately enriched in T cell function, antigen presentation, and cytokine interactions, likely impairing the adaptive and innate immune response thus favoring a pro-tumorigenic environment. Hence, germline genomic information could be used for developing non-invasive genomic tests for predicting patients’ outcomes in breast cancer.

scholarly journals Germline genetic variants associated with leukocyte-genes predict tumor recurrence in breast cancer patients

2018 ◽  
Author(s):  
Jean-Sébastien Milanese ◽  
Chabane Tibiche ◽  
Jinfeng Zou ◽  
Zhi Gang Meng ◽  
Andre Nantel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Clinical Outcomes ◽  
Genetic Variants ◽  
Cell Function ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Germline Variants ◽  
Gene Signatures ◽  
Cytokine Interactions

AbstractGermline genetic variants such as BRCA1/2 play an important role in tumorigenesis and clinical outcomes of cancer patients. However, only a small fraction (i.e., 5-10%) of inherited variants has been associated with clinical outcomes (e.g., BRCA1/2, APC, TP53, PTEN and so on). The challenge remains in using these inherited germline variants to predict clinical outcomes of cancer patient population. In an attempt to solve this issue, we applied our recently developed algorithm, eTumorMetastasis, which constructs predictive models, on exome sequencing data to ER+ breast (n=755) cancer patients. Gene signatures derived from the genes containing functionally germline genetic variants significantly distinguished recurred and non-recurred patients in two ER+ breast cancer independent cohorts (n=200 and 295, P=1.4×10−3). Furthermore, we found that recurred patients possessed a higher rate of germline genetic variants. In addition, the inherited germline variants from these gene signatures were predominately enriched in T cell function, antigen presentation and cytokine interactions, likely impairing the adaptive and innate immune response thus favoring a pro-tumorigenic environment. Hence, germline genomic information could be used for developing non-invasive genomic tests for predicting patients’ outcomes (or drug response) in breast cancer, other cancer types and even other complex diseases.

scholarly journals BREAST CANCER PATIENTS;

2013 ◽  
Vol 20 (06) ◽  
pp. 1019-1025
Author(s):  
MUHAMMAD FIAZ QAMAR ◽  
FARAH REHMAN ◽  
SABEEN ILYAS ◽  
Seher Abbas
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Small Sample Size ◽  
Brca1 Gene ◽  
Genetic Alterations ◽  
Small Sample ◽  
Diagnostic Study ◽  
Breast Cancer Patients ◽  
One Year ◽  
Exon 20

Objective: Genetic factors contribute to the high rates with breast cancer patients. Our objective was to screen themutations in the BRCA 1 gene in exon 20. Design: A diagnostic study. Place and Duration of Study: The study was carried out inmolecular biology lab, Department of Zoology, GC University Lahore and Institute of Molecular Biology and Biotechnology (IMBB),University of Lahore over a period of one year from July 2011 to Aug 2012. Patients and Methods: To screen for mutation in the BRCA1gene, blood samples were collected from 22 different patients suffering from breast cancer from the Anmol Hospital and Sir Ganga RamHospital Lahore. The collected samples were processed to screen any mutation in exon 20 which is indicative of the fact that exon 20 isnot a hotspot for mutations. Results: In our study of 22 females, we have found no mutation in the gene. It is becoming increasingly clearthat breast cancer is a multifaceted and heterogeneous disease and histopathological characteristics of breast cancer are controlled bysubsets of genetic alterations, providing convincing hints of genotypic–phenotypic correlations between morphological patterns andmolecular changes. BRCA has emerged as the master regulator of the genome through its ability to regulate and coordinate various stepsof DNA damage response. Women who carry a mutation of the gene have greatly increased chance of developing breast cancer. Thepopulation of Pakistan has been substantially screened for somatic and germline mutations in BRCA. Conclusions: Breast cancer is themost common cancer of women in Pakistan. One every 8th women is found to carry the disease. A female may develop the diseasethrough inherited mutations in the BRCA1 gene. The absence of mutation maybe attributed to small sample size of the study or may be dueto the fact that the size of the gene is so large that a single axon may not be enough to screen for mutations.

scholarly journals CDK12 inhibition enhances sensitivity of HER2+ breast cancers to HER2-TKI via suppressing PI3K/AKT

2020 ◽  
Author(s):  
Hui Li ◽  
Jinsong Wang ◽  
Zongbi Yi ◽  
Chunxiao Li ◽  
Haijuan Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
High Throughput Sequencing ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Abstract Background : While anti-HER2 tyrosine kinase inhibitors (TKIs) have radically prolonged survival and improved prognosis in HER2-positive breast cancer patients, resistance to these therapies is a constant obstacle leading to TKIs treatment failure and tumor progression.Methods : To develop new strategies to enhance TKIs efficiency by combining synergistic gene targets, we performed panel library screening using CRISPR/Cas9 knockout technique based on data mining across TCGA datasets and verified the candidate target in pre-clinical models and breast cancer high-throughput sequencing datasets.Results : We identified that CDK12, co-amplified with HER2 in a high frequency, is powerful to sensitize or re-sensitize HER2-positive breast cancer to anti-HER2 TKIs lapatinib, evidenced by patient-derived organoids (PDO) in vitro and cell-derived xenograft (CDX) or patient-derived xenograft (PDX) in vivo. Exploring mechanisms, we found that inhibition of CDK12 attenuated PI3K/AKT signal, which usually serves as an oncogenic driver and is reactivated when HER2-positive breast cancers develop resistance to lapatinib. Combining CDK12 inhibition exerted additional suppression on p-AKT activation induced by anti-HER2 TKIs lapatinib treatment. Clinically, via DNA sequencing data for tumor tissue and peripheral blood ctDNA, we found that HER2-positive breast cancer patients with CDK12 amplification responded more insensitively to anti-HER2 treatment than those without accompanying CDK12 amplification by harboring a markedly shortened progression free survival (PFS) (median PFS: 4.3 months verse 6.9 months; HR 2.26 [95% CI 1.32-3.86]; P=0.0028).Conclusions : Dual inhibition of HER2/CDK12 will prominently benefit the outcomes of HER2-positive breast cancer patients by sensitizing or re-sensitizing the tumors to anti-HER2 TKIs treatment.

scholarly journals Mutation of the PTCH1 gene predicts recurrence of breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chih-Yang Wang ◽  
Yung-Chieh Chang ◽  
Yao-Lung Kuo ◽  
Kuo-Ting Lee ◽  
Pai-Sheng Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Hedgehog Signaling ◽  
Early Recurrence ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
The Public ◽  
Protein Functions ◽  
Ptch1 Gene

Abstract Breast cancer is the most common cancer in women, and some patients develop recurrence after standard therapy. Effective predictors are urgently needed to detect recurrence earlier. The activation of Hedgehog signaling in breast cancer is correlated with poor prognosis. PTCH1 is an essential membrane receptor of Hedgehog. However, there are few reports about mutations in Hedgehog genes in breast cancer. We conducted a comprehensive study via an experimental and bioinformatics approach to detect mutated genes in breast cancer. Twenty-two breast cancer patients who developed recurrence within 24 months postoperatively were enrolled with 22 control cancer patients. Targeted deep sequencing was performed to assess the mutations among individuals with breast cancer using a panel of 143 cancer-associated genes. Bioinformatics and public databases were used to predict the protein functions of the mutated genes. Mutations were identified in 44 breast cancer specimens, and the most frequently mutated genes were BRCA2, APC, ATM, BRCA1, NF1, TET2, TSC1, TSC2, NOTCH1, MSH2, PTCH1, TP53, PIK3CA, FBXW7, and RB1. Mutation of these genes was correlated with protein phosphorylation and autophosphorylation, such as peptidyl-tyrosine and protein kinase C phosphorylation. Among these highly mutated genes, mutations of PTCH1 were associated with poor prognosis and increased recurrence of breast cancer, especially mutations in exons 22 and 23. The public sequencing data from the COSMIC database were exploited to predict the functions of the mutations. Our findings suggest that mutation of PTCH1 is correlated with early recurrence of breast cancer patients and will become a powerful predictor for recurrence of breast cancer.

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