Exome Sequencing Identifies Rare Deleterious Mutations in DNA Repair Genes FANCC and BLM as Potential Breast Cancer Susceptibility Alleles
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{"title"=>"Exome Sequencing Identifies Rare Deleterious Mutations in DNA Repair Genes FANCC and BLM as Potential Breast Cancer Susceptibility Alleles", "type"=>"journal", "authors"=>[{"first_name"=>"Ella R.", "last_name"=>"Thompson", "scopus_author_id"=>"8892870100"}, {"first_name"=>"Maria A.", "last_name"=>"Doyle", "scopus_author_id"=>"25823098100"}, {"first_name"=>"Georgina L.", "last_name"=>"Ryland", "scopus_author_id"=>"39962490800"}, {"first_name"=>"Simone M.", "last_name"=>"Rowley", "scopus_author_id"=>"37081899000"}, {"first_name"=>"David Y.H.", "last_name"=>"Choong", "scopus_author_id"=>"6603479150"}, {"first_name"=>"Richard W.", "last_name"=>"Tothill", "scopus_author_id"=>"8621899400"}, {"first_name"=>"Heather", "last_name"=>"Thorne", "scopus_author_id"=>"7003398303"}, {"first_name"=>"Daniel R.", "last_name"=>"Barnes", "scopus_author_id"=>"36717400000"}, {"first_name"=>"Jason", "last_name"=>"Li", "scopus_author_id"=>"40261884600"}, {"first_name"=>"Jason", "last_name"=>"Ellul", "scopus_author_id"=>"38461083200"}, {"first_name"=>"Gayle K.", "last_name"=>"Philip", "scopus_author_id"=>"13805187700"}, {"first_name"=>"Yoland C.", "last_name"=>"Antill", "scopus_author_id"=>"8691150700"}, {"first_name"=>"Paul A.", "last_name"=>"James", "scopus_author_id"=>"34975060200"}, {"first_name"=>"Alison H.", "last_name"=>"Trainer", "scopus_author_id"=>"15838471200"}, {"first_name"=>"Gillian", "last_name"=>"Mitchell", "scopus_author_id"=>"57197000622"}, {"first_name"=>"Ian G.", "last_name"=>"Campbell", "scopus_author_id"=>"55219980100"}], "year"=>2012, "source"=>"PLoS Genetics", "identifiers"=>{"pui"=>"365755965", "sgr"=>"84866932831", "issn"=>"15537390", "pmid"=>"23028338", "scopus"=>"2-s2.0-84866932831", "doi"=>"10.1371/journal.pgen.1002894", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)"}, "id"=>"d2832b94-f7a4-3621-984a-3461341a0048", "abstract"=>"Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.", "link"=>"http://www.mendeley.com/research/exome-sequencing-identifies-rare-deleterious-mutations-dna-repair-genes-fancc-blm-potential-breast-c-1", "reader_count"=>113, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>4, "Librarian"=>1, "Researcher"=>40, "Student > Doctoral Student"=>5, "Student > Ph. D. 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  • {"files"=>["https://ndownloader.figshare.com/files/567601"], "description"=>"<p>Males and females are represented by squares and circles, respectively. Arrows indicate individuals who underwent whole exome sequencing (families 1–3) or were the index case in subsequent mutation analysis (<i>FANCC</i> p.Asp23fs, p.Leu554Pro and p.Arg185Gln and <i>BLM</i> p.Arg899* families). Cancer-affected individuals are represented with the following symbols: breast cancer, top right quadrant filled in; bilateral breast cancer, top half; ovarian cancer, bottom left quadrant; or other cancers as indicated, centre circle. Mutation status is indicated with either the family specific mutation or wildtype (wt) under each tested individual. Age at cancer diagnosis or year of birth (b.) where known is shown for all mutation carriers. Breast cancer (BC), ovarian cancer (OC), acute leukaemia (AL), colorectal cancer (CRC), haematological malignancy (type unspecified) (Haem.), kidney cancer (KC), liver cancer (LivC), melanoma (Mel.), pancreatic cancer (PaC), prostate cancer (PrC), skin non-melanoma (Non-mel.) stomach cancer (SC), testicular cancer (TestC). Mutations indicated in parentheses indicate untested obligate carriers. Family 2 contains an individual (indicated by #) for whom mutation status is inferred assuming that non-paternity or gonadal mosaicism have not occurred.</p>", "links"=>[], "tags"=>["mutations", "familial", "cancer"], "article_id"=>238056, "categories"=>["Genetics"], "users"=>["Ella R. Thompson", "Maria A. Doyle", "Georgina L. Ryland", "Simone M. Rowley", "David Y. H. Choong", "Richard W. Tothill", "Heather Thorne", "Daniel R. Barnes", "Jason Li", "Jason Ellul", "Gayle K. Philip", "Yoland C. Antill", "Paul A. James", "Alison H. Trainer", "Gillian Mitchell", "Ian G. Campbell"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002894.g001", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_i_FANCC_i_and_i_BLM_i_mutations_identified_in_familial_breast_cancer_pedigrees_/238056", "title"=>"<i>FANCC</i> and <i>BLM</i> mutations identified in familial breast cancer pedigrees.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-09-27 02:14:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/567716"], "description"=>"a<p>Breast cancer (BC), ovarian cancer (OC), bilat. (bilateral). Age of diagnosis shown in parentheses.</p>b<p>Other cancer types observed in family branch with apparent breast cancer risk (multiple cases shown in parentheses).</p>", "links"=>[], "tags"=>["15", "high-risk", "cancer", "exome"], "article_id"=>238193, "categories"=>["Genetics"], "users"=>["Ella R. Thompson", "Maria A. Doyle", "Georgina L. Ryland", "Simone M. Rowley", "David Y. H. Choong", "Richard W. Tothill", "Heather Thorne", "Daniel R. Barnes", "Jason Li", "Jason Ellul", "Gayle K. Philip", "Yoland C. Antill", "Paul A. James", "Alison H. Trainer", "Gillian Mitchell", "Ian G. Campbell"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002894.t001", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Characteristics_of_15_high_risk_breast_cancer_families_selected_for_exome_sequencing_/238193", "title"=>"Characteristics of 15 high-risk breast cancer families selected for exome sequencing.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-09-27 02:16:33"}

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