DOCSLIB.ORG

Brca Gene Testing

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Brca Gene Testing Focusing on Personalised Medicine BRCA GENE TESTING Approximately 7-10% of breast and ovarian cancers are hereditary. BRCA1 & BRCA2 tumor suppressor genes account for a high number of these cases, but it is known that other hereditary cancer related genes are associated with the risk of developing breast and/or ovarian cancer. The BRCA Plus panel assesses 12 genes known to harbour mutations related to breast and/or ovarian cancer. The BRCA Plus analysis may identify the underlying genetic mutations that are unique to your cancer. This can help provide information on potential therapeutics, resistance to therapeutics, clinical trials and new treatments you may be able to access. What is BRCA1 & BRCA2 Testing? Around 5 – 10 % of breast cancers result from a mutation in the BRCA1 and BRCA2 genes. BRCA mutations increase the risk of developing breast and ovarian cancer, and patients with BRCA mutations tend to develop breast cancers at a younger age. Mutations in the BRCA genes can be sporadic, but they are often germline, meaning they are in all cells in your body and may be passed down to your children. Testing can be performed on a buccal swab sample which may indicate if there is a germline mutation in the BRCA gene. If the mutation is germline, family members can be tested to see if they have inherited the mutation, allowing earlier detection and prevention. BRCA Plus testing can be performed off somatic samples (tissue) in patient currently diagnosed with cancer or germline samples (blood) samples in patients who are at an elevated risk of developing cancer. Why is it important to have genomic testing if I have a family history of cancer? Testing for Inherited cancer syndromes informs clinical decision making and may assist in the prevention of adverse health out- comes. BRCA1 and BRCA2 are part of complexes involved in DNA repair using homologous recombination. Women with an abnormal BRCA1 or BRCA2 gene have up to an 80% risk of developing breast cancer by age 90 and up to 55% risk of developing ovarian cancer. In addition to breast cancer, mutations in the BRCA1/2 gene also increase the risk of ovarian, fallopian tube, pancreatic cancer, gastric cancer and prostate cancers. If there is a family history of breast cancer, other members of your family can undergo genomics testing to see if they are a carrier of germline BRCA mutations. If they are identified as a carrier of the mutations, this can enable them o:t • Start cancer screening tests earlier • Get screened for that type of cancer more often • Get screening tests that are used only for people known to be at increased cancer risk • Watch yourself closely for signs or symptoms of that kind of cancer • Learn about options to help reduce the risk of certain types of cancer, such as drugs or surgery How do I organise Testing? Download Request Receive testing kit Genomics For Life Genomics For Results sent to Form and complete from Genomics receives sample Life completes nominated health and return to for Life for testing requested testing care professional *Or Genomics For Life will arrange Genomics For Life retrieval of a tissue sample from your most recent biopsy. Toll Free: 1800 445 433 Fax: 1300 658 893 Email: [email protected] Web: www.genomicsforlife.com.au Dear Doctor, Y our patient is exploring genetic testing for their cancer and has requested Genomics For Life to perform tumour profiling . Genomics For Life is a fully NATA accredited, TGA approved, clinical diagnostic laboratory located in Brisbane. It offers a complete range of genomic testing services including comprehensive molecular tumour profiling. The service is performed with the support of the patient’s referring Doctor. Si nce 2013 we have been offering and developing a sequencing service provision for both Australian and International patients. During this time we have observed how patient outcomes can be improved when information, support and analysis are provided to both the patient and the patient’s medical team throughout the entire process of genomic testing. There are many advantages for genetic testing a patient’s tumour sample including but not limited to the following: 1. Cancer gene profiling is a powerful diagnostic tool, which may provide complimentary drug target information to the standard therapies that may have been considered or completed to the patient to date. 2. Our Genomic service comprehensively analyses the DNA and RNA of the tumour and may identify mutations that are unique and may provide prognostic and predictive information. 3. The clinical interpretation, provided by Genomics for Life, takes into account both local and up-to-date international protocols for treatment options. 4. Genomic testing provides a personalised approach to cancer treatment, which may improve patient outcome. Clinical trials of over 70,000 patients have shown that personalised therapy, based on genomic profiling of tumours, is the most effective way to improve outcome, with higher response rates, longer progression free and overall survival, and fewer deaths related to adverse events across cancers. [1-3] 5. Investing in Genomic testing may save time and money that may be spent on non-targeted/unproductive therapies. There are also a few important things to note: 1. In the majority of cases, the cost of genomics testing, is not covered by Medicare, but in some cases private health insurance may pay some benefits. We encourage the patient to check with their private fund provider. 2. Our comprehensive reports will show potential treatment options, regardless of the PBS listing, which may mean the patient may be out-of-pocket for treatment if they decide to proceed with these treatment options. 3. In some cases, the results may have implications for other family members if a clinically significant germline variant is identified. 4. Our laboratory fulfils all the local regulatory requirements to be able to offer these tests, and there is local support and interpretation of its results Genetic counselling can be arranged for your patient, by health care professionals that are conversant in genetic testing. Information can also be provided about access to clinical trials both in Australia and overseas, if required. Additional information is available on our website: www.genomicsforlife.com.au, including details on our comprehensive testing menu, including response to immune checkpoint inhibitors and cell-free (liquid biopsy) based assays. The FAQ’s contain more information on how Genomics testing may assist patient care and details of the processes involved in testing. Prior to proceeding with testing, we encourage the patient to discuss with us their budget and testing options, to ensure that we offer a solution that is both economically viable for the patient and useful for the medical practitioner. If you would like to contact us, to further discuss testing, please don’t hesitate to call us on 1800 445 433 or via email at [email protected] Kind regards, Genomics For Life 1. Jardim, D. L., et al. (2015). “Impact of a Biomarker-Based Strategy on Oncology Drug Development: A Meta-analysis of Clinical Trials Leading to FDA Approval.” J Natl Cancer Inst 107(11). 2.ReferencesSchwaederle, M., et al. (2015). “Impact of Precision Medicine in Diverse Cancers: A Meta-Analysis of Phase II Clinical Trials.” J Clin Oncol 33(32): 3817-3825 3. Subbiah, V. and R. Kurzrock (2016). “Universal genomic testing needed to win the war against cancer: Genomics is the diagnosis.” JAMA Oncology 2(6): 719-720 Phone: 1800 445 433 | Fax: 07 3054 4363 | Email: [email protected] | Web: www.genomicsforlife.com.au SOMATIC MUTATION TESTING REQUEST FORM Accredited for compliance with NPAAC Standards and ISO 15189 NATA Accreditation Number: 19325 PATIENT DETAILS ORDERING MEDICAL PRACTITIONER DETAILS Patient Surname: Doctor Name: Patient Given Name(s): Provider Number: DOB: ____ / ____ / ______ Male Female Practice Name: Patient Address: Practice Address: Contact Number: Contact Number: Email: Fax: Medicare Details: Email (for results): PATIENT INFORMED CONSENT STATEMENT MEDICAL PRACTITIONER CONSENT STATEMENT I agree to the genetic analysis and the release of my tissue and/or other By signing this form, I confirm to the best of my knowledge that I have the samples for testing. consent of the patient to request somatic and/or germline testing, and that the patient is aware that this test may require pre-payment prior to commencement of the test. Patient’s Signature: Doctor’s Signature: Date: Date: PRIVACY NOTE: The information provided will be used to assess any Medicare Beneft payable for the services rendered and to facilitate the proper administration of government health programs, and may be used to update enrolment records. Its collection is authorised by provisions of the Health Insurance Act 1973. The information may be disclosed to the Department of Health and Ageing or to a person in the medical practice associated with this claim, or as authorised/required by law. CLINICAL INFORMATION Please attach all relevant patient history and pathology reports Metastatic Disease: Yes No TEST(S) REQUESTED Comprehensive Plus Solid Tumour Analysis TSP 23TM : Melanoma, Lung & Bowel Cancer Targeted Assay Transcriptome Analysis Inherited Cancer Assay Tumour Mutational Burden Assay Cell-Free DNA Testing (dPCR - Single Probe) Sarcoma Assay Cell-Free DNA Assay PanCancer Assay Lung Assay Homologous Recombination Deficiency (HRD) Assay Colon Assay Breast Assay BRCA Somatic Assay Pharmacogenomics BRCA Germline Assay Other: Please complete all the above fields. Once the Test Requesition Form has been completed, please return to Genomics For Life along with the sample. Patient must sign consent form to perform the test. Billing Information Collection Staff Only Laboratory Use Only NOTE 1: Payment must be cleared prior to testing being performed, unless Medicare rebateble. Collection Sample Rec. Sample Type: NOTE 2: There may be out-of-pocket expenses for retrieval of slides imposed by other laboratories that may Date: Type: Date: (Exp Date) be charged to the patient.
Load more

Recommended publications
  • Insights Into Regulation of Human RAD51 Nucleoprotein Filament Activity During
    Insights into Regulation of Human RAD51 Nucleoprotein Filament Activity During Homologous Recombination Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Ravindra Bandara Amunugama, B.S. Biophysics Graduate Program The Ohio State University 2011 Dissertation Committee: Richard Fishel PhD, Advisor Jeffrey Parvin MD PhD Charles Bell PhD Michael Poirier PhD Copyright by Ravindra Bandara Amunugama 2011 ABSTRACT Homologous recombination (HR) is a mechanistically conserved pathway that occurs during meiosis and following the formation of DNA double strand breaks (DSBs) induced by exogenous stresses such as ionization radiation. HR is also involved in restoring replication when replication forks have stalled or collapsed. Defective recombination machinery leads to chromosomal instability and predisposition to tumorigenesis. However, unregulated HR repair system also leads to similar outcomes. Fortunately, eukaryotes have evolved elegant HR repair machinery with multiple mediators and regulatory inputs that largely ensures an appropriate outcome. A fundamental step in HR is the homology search and strand exchange catalyzed by the RAD51 recombinase. This process requires the formation of a nucleoprotein filament (NPF) on single-strand DNA (ssDNA). In Chapter 2 of this dissertation I describe work on identification of two residues of human RAD51 (HsRAD51) subunit interface, F129 in the Walker A box and H294 of the L2 ssDNA binding region that are essential residues for salt-induced recombinase activity. Mutation of F129 or H294 leads to loss or reduced DNA induced ATPase activity and formation of a non-functional NPF that eliminates recombinase activity. DNA binding studies indicate that these residues may be essential for sensing the ATP nucleotide for a functional NPF formation.
    [Show full text]
  • RAD51L3 (1-216, His-Tag) Human Protein – AR51328PU-S | Origene
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for AR51328PU-S RAD51L3 (1-216, His-tag) Human Protein Product data: Product Type: Recombinant Proteins Description: RAD51L3 (1-216, His-tag) human recombinant protein, 0.1 mg Species: Human Expression Host: E. coli Tag: His-tag Predicted MW: 23.9 kDa Concentration: lot specific Purity: >95% by SDS - PAGE Buffer: Presentation State: Purified State: Liquid purified protein Buffer System: 20 mM Tris-HCl buffer (pH 8.0) containing 0.4M Urea, 10% glycerol Preparation: Liquid purified protein Protein Description: Recombinant human RDA51D protein, fused to His-tag at N-terminus, was expressed in E.coli. Storage: Store undiluted at 2-8°C for one week or (in aliquots) at -20°C to -80°C for longer. Avoid repeated freezing and thawing. Stability: Shelf life: one year from despatch. RefSeq: NP_001136043 Locus ID: 5892 UniProt ID: O75771 Cytogenetics: 17q12 Synonyms: BROVCA4; R51H3; RAD51L3; TRAD This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 2 RAD51L3 (1-216, His-tag) Human Protein – AR51328PU-S Summary: The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA.
    [Show full text]
  • University of Cincinnati
    UNIVERSITY OF CINCINNATI Date:__09/27/2004_________________ I, _Katherine L. Lillard___________________________, hereby submit this work as part of the requirements for the degree of: Doctor of Philosophy in: Molecular Genetics, Biochemistry, and Microbiology It is entitled: The BLM helicase functions in alternative lengthening of telomeres. This work and its defense approved by: Chair: Joanna Groden____________ Iain Cartwright__________ Carolyn Price____________ James Stringer___________ Kathleen Dixon___________ THE BLM HELICASE FUNCTIONS IN ALTERNATIVE LENGTHENING OF TELOMERES A dissertation submitted to the Division of Research and Advanced Studies Of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY (Ph.D.) In the Department of Molecular Genetics, Biochemistry & Microbiology Of the College of Medicine 2004 by Kate Lillard-Wetherell B.S., University of Texas at Austin, 1998 Committee Chair: Joanna Groden, Ph.D. ABSTRACT Somatic cells from persons with the inherited chromosome breakage syndrome Bloom syndrome (BS) feature excessive chromosome breakage, intra-and inter- chromosomal homologous exchanges and telomeric associations. The gene mutated in BS, BLM, encodes a RecQ-like ATP-dependent 3’-to-5’ helicase that presumably functions in some types of DNA transactions. As the absence of BLM is associated with excessive recombination, in vitro experiments have tested the ability of BLM to suppress recombination and/or resolve recombination intermediates. In vitro, BLM promotes branch migration of Holliday junctions, resolves D-loops and unwinds G-quadruplex DNA. A function for BLM in maintaining telomeres is suggested by the latter, since D- loops and perhaps G-quadruplex structures are thought to be present at telomeres. In the present study, the association of BLM with telomeres was investigated.
    [Show full text]
  • Recombinational DNA Repair and Human Disease Larry H
    Mutation Research 509 (2002) 49–78 Recombinational DNA repair and human disease Larry H. Thompson a,∗, David Schild b a Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory L-441, P.O. Box 808, Livermore, CA 94551-0808, USA b Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA Abstract We review the genes and proteins related to the homologous recombinational repair (HRR) pathway that are implicated in cancer through either genetic disorders that predispose to cancer through chromosome instability or the occurrence of somatic mutations that contribute to carcinogenesis. Ataxia telangiectasia (AT),Nijmegen breakage syndrome (NBS), and an ataxia-like disorder (ATLD), are chromosome instability disorders that are defective in the ataxia telangiectasia mutated (ATM), NBS, and Mre11 genes, respectively. These genes are critical in maintaining cellular resistance to ionizing radiation (IR), which kills largely by the production of double-strand breaks (DSBs). Bloom syndrome involves a defect in the BLM helicase, which seems to play a role in restarting DNA replication forks that are blocked at lesions, thereby promoting chromosome stability. The Werner syndrome gene (WRN) helicase, another member of the RecQ family like BLM, has very recently been found to help mediate homologous recombination. Fanconi anemia (FA) is a genetically complex chromosomal instability disorder involving seven or more genes, one of which is BRCA2. FA may be at least partially caused by the aberrant production of reactive oxidative species. The breast cancer-associated BRCA1 and BRCA2 proteins are strongly implicated in HRR; BRCA2 associates with Rad51 and appears to regulate its activity. We discuss in detail the phenotypes of the various mutant cell lines and the signaling pathways mediated by the ATM kinase.
    [Show full text]
  • Association Between Genetic Variants in DNA Double-Strand Break
    Cancers 2016, 8, 23 S1 of S4 Supplementary Material: Association between Genetic Variants in DNA Double-Strand Break Repair Pathways and Risk of Radiation Therapy-Induced Pneumonitis and Esophagitis in Non-Small Cell Lung Cancer Lina Zhao, Xia Pu, Yuanqing Ye, Charles Lu, Joe Y. Chang and Xifeng Wu Table S1. Genes in DSB repair pathway included in this study. Gene Symbol Chr Number of SNPs Included APTX 9 1 ATM 11 10 BLM 15 23 BRCA1 17 10 BRCA2 13 27 BRIP1 17 13 CHEK1 11 8 CLSPN 1 4 DCLRE1C 10 14 DMC1 22 4 EME1 17 10 EXO1 1 24 LIG1 19 11 LIG3 17 6 LIG4 13 12 MDC1 6 5 MRE11A 11 5 MUS81 11 6 NBN 8 14 PNKP 19 5 PRKDC 8 11 RAD50 5 5 RAD51 15 5 RAD51C 17 6 RAD51L3 17 7 RAD52 12 19 RAD54B 8 7 RAD54L 1 9 RAG1 11 4 RAG2 11 4 RPA1 17 17 RPA2 1 6 RPA3 7 30 RPA4 X 3 SHFM1 7 7 SMC1L1 X 1 SPO11 20 1 Cancers 2016, 8, 23 S2 of S4 Table S1. Cont. Gene Symbol Chr Number of SNPs Included TOPBP1 3 10 TP53BP1 15 6 XLF 2 7 XRCC2 7 10 XRCC3 14 6 XRCC4 5 21 XRCC5 2 25 XRCC6 22 1 Table S2. SNPs in DSB pathway associated with the risk of esophagitis (50 SNPS). SNP Gene Genotype Chromosome Model OR (95% CI) p Value rs799923 BRCA1 G > A 17 ADD 0.39 (0.22–0.69) 0.001 rs16945643 BRIP1 A > G 17 ADD 0.2 (0.08–0.53) 0.001 rs2797604 EXO1 A > G 1 DOM 0.29 (0.13–0.64) 0.002 rs6413436 RAD52 A > G 12 DOM 0.34 (0.16–0.69) 0.003 rs3786136 RPA1 G > A 17 ADD 2.64 (1.4–4.97) 0.003 rs4149909 EXO1 A > G 1 DOM 0.15 (0.04–0.56) 0.004 rs1592159 DCLRE1C A > G 10 ADD 0.49 (0.3–0.81) 0.005 rs10744729 RAD52 C > A 12 DOM 0.33 (0.15–0.71) 0.005 rs4149963 EXO1 G > A 1 DOM 6.39 (1.71–23.89)
    [Show full text]
  • Gene Expression Effects of Lithium and Valproic Acid in a Serotonergic Cell Line
    bioRxiv preprint doi: https://doi.org/10.1101/227652; this version posted December 1, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Gene expression effects of lithium and valproic acid in a serotonergic cell line. Diana Balasubramanian1, John F. Pearson2, Martin A. Kennedy1 1Gene Structure and Function Laboratory and Carney Centre for Pharmacogenomics, Department of Pathology, University of Otago, Christchurch, New Zealand2 2Biostatistics and Computational Biology unit, University of Otago, Christchurch. Correspondence to: Prof. M. A. Kennedy Department of Pathology University of Otago, Christchurch Christchurch, New Zealand Email: [email protected] Keywords: RNA-Seq, valproic acid, gene expression, mood stabilizer, pharmacogenomics bioRxiv preprint doi: https://doi.org/10.1101/227652; this version posted December 1, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Valproic acid (VPA) and lithium are widely used in the treatment of bipolar disorder. However, the underlying mechanism of action of these drugs is not clearly understood. We used RNA-Seq analysis to examine the global profile of gene expression in a rat serotonergic cell line (RN46A) after exposure to these two mood stabilizer drugs. Numerous genes were differentially regulated in response to VPA (log2 fold change ≥ 1.0; i.e.
    [Show full text]
  • Genome-Wide Analysis of Organ-Preferential Metastasis of Human Small Cell Lung Cancer in Mice
    Vol. 1, 485–499, May 2003 Molecular Cancer Research 485 Genome-Wide Analysis of Organ-Preferential Metastasis of Human Small Cell Lung Cancer in Mice Soji Kakiuchi,1 Yataro Daigo,1 Tatsuhiko Tsunoda,2 Seiji Yano,3 Saburo Sone,3 and Yusuke Nakamura1 1Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; 2Laboratory for Medical Informatics, SNP Research Center, Riken (Institute of Physical and Chemical Research), Tokyo, Japan; and 3Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima School of Medicine, Tokushima, Japan Abstract Molecular interactions between cancer cells and their Although a number of molecules have been implicated in microenvironment(s) play important roles throughout the the process of cancer metastasis, the organ-selective multiple steps of metastasis (5). Blood flow and other nature of cancer cells is still poorly understood. To environmental factors influence the dissemination of cancer investigate this issue, we established a metastasis model cells to specific organs (6). However, the organ specificity of in mice with multiple organ dissemination by i.v. injection metastasis (i.e., some organs preferentially permit migration, of human small cell lung cancer (SBC-5) cells. We invasion, and growth of specific cancer cells, but others do not) analyzed gene-expression profiles of 25 metastatic is a crucial determinant of metastatic outcome, and proteins lesions from four organs (lung, liver, kidney, and bone) involved in the metastatic process are considered to be using a cDNA microarray representing 23,040 genes and promising therapeutic targets. extracted 435 genes that seemed to reflect the organ More than a century ago, Stephen Paget suggested that the specificity of the metastatic cells and the cross-talk distribution of metastases was not determined by chance, but between cancer cells and microenvironment.
    [Show full text]
  • 132608682.Pdf
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Plymouth Electronic Archive and Research Library THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 278, No. 48, Issue of November 28, pp. 48357–48366, 2003 © 2003 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. Functional Interaction between the Bloom’s Syndrome Helicase and the RAD51 Paralog, RAD51L3 (RAD51D)* Received for publication, August 11, 2003, and in revised form, September 12, 2003 Published, JBC Papers in Press, September 15, 2003, DOI 10.1074/jbc.M308838200 Jeremy P. Braybrooke‡§, Ji-Liang Li‡§, Leonard Wu‡, Fiona Caple¶, Fiona E. Benson¶, and Ian D. Hickson‡ʈ From ‡Cancer Research UK, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom and the ¶Department of Biological Sciences, Lancaster Environment Centre, Lancaster University, Lancaster LA1 4YQ, United Kingdom Bloom’s syndrome (BS) is a genetic disorder associ- and plating, and a strikingly high level of chromosomal insta- ated with short stature, fertility defects, and a predispo- bility (3, 4). The characteristic feature of BS cells, which is used Downloaded from sition to the development of cancer. BS cells are char- in diagnosis of the disorder, is an elevated frequency of genetic acterized by genomic instability; in particular, a high recombination events, particularly sister-chromatid exchanges rate of reciprocal exchanges between sister-chromatids (SCEs) (5). However, this hyper-recombination is not limited to and homologous chromosomes. The BS gene product, exchanges between sister-chromatids, because interchromo- BLM, is a helicase belonging to the highly conserved somal homologous recombination also occurs at an elevated RecQ family.
    [Show full text]
  • Worldwide Genetic Structure in 37 Genes Important in Telomere Biology
    Heredity (2012) 108, 124–133 & 2012 Macmillan Publishers Limited All rights reserved 0018-067X/12 www.nature.com/hdy ORIGINAL ARTICLE Worldwide genetic structure in 37 genes important in telomere biology L Mirabello1, M Yeager2, S Chowdhury2,LQi2, X Deng2, Z Wang2, A Hutchinson2 and SA Savage1 1Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA and 2Core Genotyping Facility, National Cancer Institute, Division of Cancer Epidemiology and Genetics, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD, USA Telomeres form the ends of eukaryotic chromosomes and and differentiation were significantly lower in telomere are vital in maintaining genetic integrity. Telomere dysfunc- biology genes compared with the innate immunity genes. tion is associated with cancer and several chronic diseases. There was evidence of evolutionary selection in ACD, Patterns of genetic variation across individuals can provide TERF2IP, NOLA2, POT1 and TNKS in this data set, which keys to further understanding the evolutionary history of was consistent in HapMap 3. TERT had higher than genes. We investigated patterns of differentiation and expected levels of haplotype diversity, likely attributable to population structure of 37 telomere maintenance genes a lack of linkage disequilibrium, and a potential cancer- among 53 worldwide populations. Data from 898 unrelated associated SNP in this gene, rs2736100, varied substantially individuals were obtained from the genome-wide scan of the in genotype frequency across major continental regions. It is Human Genome Diversity Panel (HGDP) and from 270 possible that the genes under selection could influence unrelated individuals from the International HapMap Project telomere biology diseases.
    [Show full text]
  • Mutational Analysis of Thirty-Two Double-Strand DNA Break Repair Genes in Breast and Pancreatic Cancers
    Priority Report Mutational Analysis of Thirty-two Double-Strand DNA Break Repair Genes in Breast and Pancreatic Cancers Xianshu Wang,1 Csilla Szabo,1 Chiping Qian,3 Peter G. Amadio,1 Stephen N. Thibodeau,1 James R. Cerhan,2 Gloria M. Petersen,2 Wanguo Liu,3 and Fergus J. Couch1 Departments of 1Laboratory Medicine and Pathology and 2Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota and 3Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana Abstract that mutations in other DNA damage repair genes may predispose and/or contribute to breast cancer. Similarly, the recent discovery Inactivating mutations in several genes that encode compo- BRCA2, FANCC FANCG nents of the DNA repair machinery have been associated with that mutations in , and (2, 11, 12) are an increased risk of breast cancer. To assess whether associated with pancreatic cancer suggests that mutations in other alterations in other DNA repair genes contribute to breast repair genes may contribute to pancreatic cancer risk. To identify cancer and to further determine the relevance of these genes other DNA repair genes associated with breast and pancreatic to pancreatic cancer, we performed mutational analysis of 32 cancer, we performed a mutation screen of the coding regions of 32 genes involved in DSB signaling and repair in 38 breast tumors, DNA double-strand break repair genes in genomic DNA from BRCA1/ BRCA1/ 48 pancreatic tumors, and germline DNA from 10 non- 38 breast tumors, 48 pancreatic tumors, and 10 non- BRCA2 BRCA2 hereditary breast cancer patients. A total of 494 coding hereditary breast cancer patients.
    [Show full text]
  • Essential Role of Microphthalmia Transcription Factor for DNA Replication, Mitosis and Genomic Stability in Melanoma
    Oncogene (2011) 30, 2319–2332 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc ORIGINAL ARTICLE Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma T Strub1,4, S Giuliano2,4,TYe1, C Bonet2, C Keime1, D Kobi1, S Le Gras1, M Cormont3, R Ballotti2, C Bertolotto2 and I Davidson1 1Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire, CNRS, INSERM, Universite´ de Strasbourg, Illkirch, France; 2INSERM U895 Team 1 and Department of Dermatology, CHU Nice, France and 3INSERM U895 Team 7, Nice, France Malignant melanoma is an aggressive cancer known use of internal promoters (Steingrimsson, 2008). The for its notorious resistance to most current therapies. MITF-M isoform (hereafter designated simply as The basic helix-loop-helix microphthalmia transcription MITF) is the major form produced specifically in the factor (MITF) is the master regulator determining the melanocyte lineage from an intronic promoter (Goding, identity and properties of the melanocyte lineage, and is 2000b). MITF is essential for the survival of melano- regarded as a lineage-specific ‘oncogene’ that has a blasts and postnatal melanocytes (McGill et al., 2002; critical role in the pathogenesis of melanoma. MITF Hou and Pavan, 2008), in which it also controls the promotes melanoma cell proliferation, whereas sustained expression of genes required for the melanin synthesis supression of MITF expression leads to senescence. (Bertolotto et al., 1998). By combining chromatin immunoprecipitation coupled to In addition to regulating multiple aspects of normal high throughput sequencing (ChIP-seq) and RNA sequen- melanocyte function, MITF also has a critical role in cing analyses, we show that MITF directly regulates a melanoma, in which it is required for survival, and set of genes required for DNA replication, repair and controls the proliferation, invasive and metastatic mitosis.
    [Show full text]
  • Association of XRCC3 and XRCC4 Gene Polymorphisms, Family History
    Journal of Human Genetics (2013) 58, 679–685 & 2013 The Japan Society of Human Genetics All rights reserved 1434-5161/13 www.nature.com/jhg ORIGINAL ARTICLE Association of XRCC3 and XRCC4 gene polymorphisms, family history of cancer and tobacco smoking with non-small-cell lung cancer in a Chinese population: a case–control study Fei He1, Shen-Chih Chang2, Gina Maria Wallar2, Zuo-Feng Zhang2 and Lin Cai1 Single-nucleotide polymorphisms (SNPs) of DNA repair genes have been reported to modify cancer risk. This study aimed to determine SNPs of the DNA repair genes X-ray repair cross-complementing group 3 (XRCC3) and X-ray cross-complementing group 4 (XRCC4) and their association with non-small-cell lung cancer (NSCLC) susceptibility in a Chinese population. A total of 507 NSCLC patients and 662 healthy controls were recruited for genotyping. Epidemiological and clinical data were also collected for association studies. The data showed that the rs1799794 G allele in the XRCC3 gene and minor allele carriers of XRCC4, including rs1056503 and rs9293337, were inversely associated with NSCLC risk (GG vs homozygote AA), whereas the rs861537 AG or AA genotype and XRCC4 rs6869366 had a significantly increased NSCLC risk. Furthermore, tobacco smoking over 26 pack-years, a family history of lung cancer, exposure to environmental tobacco smoke (ETS) and negative mental status were risk factors for developing NSCLC. This study suggests that SNPs of XRCC3 and XRCC4 and other environmental factors are risk factors for developing NSCLC in this Chinese Han population. Journal of Human Genetics (2013) 58, 679–685; doi:10.1038/jhg.2013.78; published online 8 August 2013 Keywords: case–control study; non-small-cell lung cancer; single-nucleotide polymorphism; XRCC3 and XRCC4 INTRODUCTION homologous recombination and non-homologous end-joining DNA Lung cancer was the most commonly diagnosed cancer and the repairs.
    [Show full text]