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Hereditary genetic susceptibility to cancer

M Lee, N P S Crawford
Cancer is estimated to be responsible for 8 million deaths worldwide and over half a million deaths every year in the United States. The majority of cancer-related deaths in solid tumors is directly associated with the effects of metastasis. While the influence of germline factors on cancer risk and development has long been recognized, the contribution of hereditary variation to tumor progression and metastasis has only gained acceptance more recently. A variety of approaches have been used to define how hereditary variation influences tumor progression and metastasis...
2016: Advances in Cancer Research
Valentina Zampiga, Rita Danesi, Gianluca Tedaldi, Michela Tebaldi, Ilaria Cangini, Francesca Pirini, Cristina Pittureri, Elena Amaducci, Luciano Guidi, Marina Faedi, Dino Amadori, Fabio Falcini, Daniele Calistri
Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder occurring at a young age that predisposes individuals to multiple forms of cancer and to a heterogeneous spectrum of malignancies. We describe the clinical history of a patient who had 5 primary malignant cancers and a familiar history consistent with LFS. We analyzed the genomic DNA of the proband and her relatives by next-generation sequencing (NGS) technology using an enrichment protocol for the simultaneous sequencing of 94 genes involved in hereditary cancers...
August 5, 2016: International Journal of Biological Markers
David J Hermel, Wendy C McKinnon, Marie E Wood, Marc S Greenblatt
This study explores our Familial Cancer Program's experience implementing multi-gene panel testing in a largely rural patient population. We conducted a retrospective review of patients undergoing panel testing between May 2011 and August 2015. Our goal was to evaluate factors that might be predictors of identifying variants (pathogenic or uncertain significance) and to assess clinical management changes due to testing. We utilized a structured family history tool to determine the significance of patient's family histories with respect to identification of genetic variants...
July 11, 2016: Familial Cancer
Joonyoung Her, Nam Soo Lee, Yonghwan Kim, Hongtae Kim
Sustaining genomic integrity is essential for preventing onset of cancers. Therefore, human cells evolve to have refined biological pathways to defend genetic materials from various genomic insults. DNA damage response and DNA repair pathways essential for genome maintenance are accomplished by cooperative executions of multiple factors including breast cancer type 1 susceptibility protein (BRCA1). BRCA1 is initially identified as an altered gene in the hereditary breast cancer patients. Since then, tremendous efforts to understand the functions of BRAC1 reveal that BRCA1 is found in distinct complexes, including BRCA1-A, BRCA1-B, BRCA1-C, and the BRCA1/PALB2/BRCA2 complex, and plays diverse roles in a context-dependent manner...
July 2016: Acta Biochimica et Biophysica Sinica
Thomas C Randall, Katrina Armstrong
Ovarian cancer is an uncommon but deadly disease. There is no effective screening for the disease, and the majority of women with ovarian cancer present in advanced stage and eventually die from their disease. The majority of families with multiple cases of breast and ovarian cancer are found to carry germline mutations in BRCA1/2. Recent, more sensitive sequencing techniques have shown that nearly 20 % of ovarian cancer is associated with germline mutations in cancer susceptibility genes, with approximately 15 % accounted for by deleterious mutations in BRCA1/2...
August 2016: Current Treatment Options in Oncology
Milena Flória-Santos, Luís Carlos Lopes-Júnior, Larissa de Melo Alvarenga, Mayara Segundo Ribeiro, Victor Evangelista de Faria Ferraz, Lucila Castanheira Nascimento, Gabriela Pereira-da-Silva
Analysis of cancer family history (CFH) offers a low-cost genetic tool to identify familial cancer predisposition. In middle-income settings, the scarcity of individual records and database-linked records hinders the assessment of self-reported CFH consistency as an indicator of familial cancer predisposition. We used self-reported CFH to identify those families at risk for hereditary cancer syndromes in community-based primary care centers of a low-income Brazilian area. We also evaluated the consistency of the information collected by reassessing CFH five years later...
June 3, 2016: Genetics and Molecular Biology
Ava Kwong
Genetic screening for hereditary breast and ovarian cancer (HBOC) has gained much attention for the past decades. With the development of advanced sequencing technology, other novel breast cancer associated susceptibility genes, other than BRCA genes, have been identified recently. The prevalence of BRCA mutation is known to be different in the West and in the East, therefore it is important to understand the mutation spectrum locally and in Asia to improve early diagnosis and clinical management of hereditary breast cancer in the region...
June 2016: Chinese Clinical Oncology
Filipa Lynce, Claudine Isaacs
The traditional model by which an individual was identified as harboring a hereditary susceptibility to cancer was to test for a mutation in a single gene or a finite number of genes associated with a particular syndrome (e.g., BRCA1 and BRCA2 for hereditary breast and ovarian cancer or mismatch repair genes for Lynch syndrome). The decision regarding which gene or genes to test for was based on a review of the patient's personal medical history and their family history. With advances in next-generation DNA sequencing technology, offering simultaneous testing for multiple genes associated with a hereditary susceptibility to cancer is now possible...
2016: American Society of Clinical Oncology Educational Book
Roxana Moslehi, Elizabeth Freedman, Nur Zeinomar, Carmela Veneroso, Paul H Levine
BACKGROUND: To assess the importance of heredity in the etiology of inflammatory breast cancer (IBC), we compared IBC patients to several carefully chosen comparison groups with respect to the prevalence of first-degree family history of breast cancer. METHODS: IBC cases (n = 141) were compared to non-inflammatory breast cancer cases (n = 178) ascertained through George Washington University (GWU) with respect to the prevalence of first-degree family history of breast cancer and selected environmental/lifestyle risk factors for breast cancer...
2016: BMC Cancer
Madison R Chandler, Erin P Bilgili, Nancy D Merner
Inherited genetic risk factors contribute toward breast cancer (BC) onset. BC risk variants can be divided into three categories of penetrance (high, moderate, and low) that reflect the probability of developing the disease. Traditional BC susceptibility gene discovery approaches that searched for high- and moderate-risk variants in familial BC cases have had limited success; to date, these risk variants explain only ∼30% of familial BC cases. Next-generation sequencing technologies can be used to search for novel high and moderate BC risk variants, and this manuscript reviews 12 familial BC whole-exome sequencing efforts...
September 2016: Human Mutation
David W Collins, Harini V Gudiseva, Benjamin Trachtman, Anita S Bowman, Anna Sagaser, Prithvi Sankar, Eydie Miller-Ellis, Amanda Lehman, Victoria Addis, Joan M O'Brien
PURPOSE: To estimate the population frequencies of all common mitochondrial variants and ancestral haplogroups among 1,999 subjects recruited for the Primary Open-Angle African American Glaucoma Genetics (POAAGG) Study, including 1,217 primary open-angle glaucoma (POAG) cases and 782 controls, and to identify ancestral subpopulations and mitochondrial mutations as potential risk factors for POAG susceptibility. METHODS: Subject classification by characteristic glaucomatous optic nerve findings and corresponding visual field defects, as defined by enrolling glaucoma specialists, stereo disc photography, phlebotomy, extraction of total DNA from peripheral blood or saliva, DNA quantification and normalization, PCR amplification of whole mitochondrial genomes, Ion Torrent deep semiconductor DNA sequencing on DNA pools ("Pool-seq"), Sanger sequencing of 3,479 individual mitochondrial DNAs, and bioinformatic analysis...
2016: Molecular Vision
Israel Gomy, Maria Del Pilar Estevez Diz
Hereditary cancer risk assessment is a multidisciplinary and dynamic process, with the purpose of estimating probabilities of germline mutations in cancer susceptibility genes and assessing empiric risks of cancer based on personal and family histories, in order to offer clinical and molecular diagnoses and clinical management based on these risks. Genetic tests are available and most of them are reimbursed by insurance companies, although they are generally not covered by the public health systems of developing countries...
May 13, 2016: Genetics and Molecular Biology
Tomas Lindahl, Paul Modrich, Aziz Sancar
The Royal Swedish Academy awarded the Nobel Prize in Chemistry for 2015 to Tomas Lindahl, Paul Modrich and Aziz Sancar for their discoveries in fundamental mechanisms of DNA repair. This pioneering research described three different essential pathways that correct DNA damage, safeguard the integrity of the genetic code to ensure its accurate replication through generations, and allow proper cell division. Working independently of each other, Tomas Lindahl, Paul Modrich and Aziz Sancar delineated the mechanisms of base excision repair, mismatch repair and nucleotide excision repair, respectively...
2016: Journal of the Association of Genetic Technologists
H X Peng, X Xu, R Yang, Y M Chu, D M Yang, Y Xu, F L Zhou, W Z Ma, X J Zhang, M Guan, Z H Yang, Z D Jin
Single nucleotide polymorphisms (SNPs) in mismatch repair genes, especially in the MLH1 gene, are closely associated with susceptibility to hereditary nonpolyposis colorectal cancer. However, few relevant findings are available regarding the association between sporadic colorectal cancer (SCRC) and SNPs of MLH1 in Chinese patients. Therefore, the present study aimed to describe the pathogenic association between three important MLH1 polymorphisms and SCRC in the Chinese population. Peripheral blood samples from 156 SCRC patients and 311 healthy controls were collected...
2016: Genetics and Molecular Research: GMR
Kara N Maxwell, Steven N Hart, Joseph Vijai, Kasmintan A Schrader, Thomas P Slavin, Tinu Thomas, Bradley Wubbenhorst, Vignesh Ravichandran, Raymond M Moore, Chunling Hu, Lucia Guidugli, Brandon Wenz, Susan M Domchek, Mark E Robson, Csilla Szabo, Susan L Neuhausen, Jeffrey N Weitzel, Kenneth Offit, Fergus J Couch, Katherine L Nathanson
Sequencing tests assaying panels of genes or whole exomes are widely available for cancer risk evaluation. However, methods for classification of variants resulting from this testing are not well studied. We evaluated the ability of a variant-classification methodology based on American College of Medical Genetics and Genomics (ACMG) guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG-designated reportable cancer and non-cancer-associated genes, in individuals who met guidelines for hereditary cancer risk evaluation...
May 5, 2016: American Journal of Human Genetics
Benjamin G Challis, Narayanan Kandasamy, Andrew S Powlson, Olympia Koulouri, Anand Kumar Annamalai, Lisa Happerfield, Alison J Marker, Mark J Arends, Serena Nik-Zainal, Mark Gurnell
CONTEXT: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Although the majority of childhood ACC arises in the context of inherited cancer susceptibility syndromes, it remains less clear whether a hereditary tumor predisposition exists for the development of ACC in adults. Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation. CASE: A 54-year-old female with a history of ovarian and colorectal malignancy was found to have an ACC...
June 2016: Journal of Clinical Endocrinology and Metabolism
Christine Stanislaw, Yuan Xue, William R Wilcox
The introduction of next-generation sequencing (NGS) technology in testing for hereditary cancer susceptibility allows testing of multiple cancer susceptibility genes simultaneously. While there are many potential benefits to utilizing this technology in the hereditary cancer clinic, including efficiency of time and cost, there are also important limitations that must be considered. The best panel for the given clinical situation should be selected to minimize the number of variants of unknown significance...
March 2016: Cancer Biology & Medicine
M Borecka, P Zemankova, M Vocka, P Soucek, J Soukupova, P Kleiblova, J Sevcik, Z Kleibl, M Janatova
Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among common solid cancer diagnoses. It has been shown that up to 10% of PDAC cases have a familial component. Characterization of PDAC-susceptibility genes could reveal high-risk individuals and patients that may benefit from tailored therapy. Hereditary mutations in PALB2 (Partner and Localizer of BRCA2) gene has been shown to predispose, namely to PDAC and breast cancers; however, frequencies of mutations vary among distinct geographical populations...
May 2016: Cancer Genetics
Víctor M Valdespino-Gómez, Víctor E Valdespino-Castillo
More than 200 cancer susceptibility syndromes (CSS) have been recognized through performing classic epidemiologic studies and genetic linkage analysis. In most CSSs clinical conditions of the patients have been identified as well as their hereditary patterns and the predisponent genes to cancer development. Cancer hereditary identification is a useful condition, since cancer family integrants may benefit of efficient strategies in early screening and in tumor prevention strategies; this consultation is performed by oncogenetic molecular medical consultants who must be scientifically competent for Human Genetics and Cancer molecular biology domains...
May 2016: Revista Médica del Instituto Mexicano del Seguro Social
Bryce A Seifert, Julianne M O'Daniel, Krunal Amin, Daniel S Marchuk, Nirali M Patel, Joel S Parker, Alan P Hoyle, Lisle E Mose, Andrew Marron, Michele C Hayward, Christopher Bizon, Kirk C Wilhelmsen, James P Evans, H Shelton Earp, Norman E Sharpless, D Neil Hayes, Jonathan S Berg
PURPOSE: To evaluate germline variants in hereditary cancer susceptibility genes among unselected cancer patients undergoing tumor-germline sequencing. EXPERIMENTAL DESIGN: Germline sequence data from 439 individuals undergoing tumor-germline dyad sequencing through the LCCC1108/UNCseq™ (NCT01457196) study were analyzed for genetic variants in 36 hereditary cancer susceptibility genes. These variants were analyzed as an exploratory research study to determine whether pathogenic variants exist within the germline of patients undergoing tumor-germline sequencing...
August 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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