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dc.contributor.authorMuranen, Taru Aen
dc.contributor.authorGreco, Darioen
dc.contributor.authorBlomqvist, Carlen
dc.contributor.authorAittomäki, Kristiinaen
dc.contributor.authorKhan, Sofiaen
dc.contributor.authorHogervorst, Fransen
dc.contributor.authorVerhoef, Sennoen
dc.contributor.authorPharoah, Paulen
dc.contributor.authorDunning, Alisonen
dc.contributor.authorShah, Mitulen
dc.contributor.authorLuben, Roberten
dc.contributor.authorBojesen, Stig Een
dc.contributor.authorNordestgaard, Børge Gen
dc.contributor.authorSchoemaker, Minouken
dc.contributor.authorSwerdlow, Anthonyen
dc.contributor.authorGarcía-Closas, Montserraten
dc.contributor.authorFigueroa, Jonineen
dc.contributor.authorDörk, Thiloen
dc.contributor.authorBogdanova, Natalia Ven
dc.contributor.authorHall, Peren
dc.contributor.authorLi, Jingmeien
dc.contributor.authorKhusnutdinova, Elzaen
dc.contributor.authorBermisheva, Marinaen
dc.contributor.authorKristensen, Vesselaen
dc.contributor.authorBorresen-Dale, Anne-Liseen
dc.contributor.authorNBCS, Investigatorsen
dc.contributor.authorPeto, Julianen
dc.contributor.authordos, Santos Silva Isabelen
dc.contributor.authorCouch, Fergus Jen
dc.contributor.authorOlson, Janet Een
dc.contributor.authorHillemans, Peteren
dc.contributor.authorPark-Simon, Tjoung-Wonen
dc.contributor.authorBrauch, Hiltruden
dc.contributor.authorHamann, Uteen
dc.contributor.authorBurwinkel, Barbaraen
dc.contributor.authorMarme, Frederiken
dc.contributor.authorMeindl, Alfonsen
dc.contributor.authorSchmutzler, Rita Ken
dc.contributor.authorCox, Angelaen
dc.contributor.authorCross, Simon Sen
dc.contributor.authorSawyer, Elinor Jen
dc.contributor.authorTomlinson, Ianen
dc.contributor.authorLarechts, Dietheren
dc.contributor.authorMoisse, Matthieuen
dc.contributor.authorLindblom, Annikaen
dc.contributor.authorMargolin, Saraen
dc.contributor.authorHollestelle, Antoinetteen
dc.contributor.authorMartens, John WMen
dc.contributor.authorFasching, Peter Aen
dc.contributor.authorBeckmann, Matthias Wen
dc.contributor.authorAndrulis, Irene Len
dc.contributor.authorKnight, Julia Aen
dc.contributor.authorkConFab/AOCS, Investigatorsen
dc.contributor.authorAnton-Culver, Hodaen
dc.contributor.authorZiogas, Argyriosen
dc.contributor.authorGiles, Graham Gen
dc.contributor.authorMilne, Roger Len
dc.contributor.authorBrenner, Hermannen
dc.contributor.authorArndt, Volkeren
dc.contributor.authorMannermaa, Artoen
dc.contributor.authorKosma, Veli-Mattien
dc.contributor.authorChang-Claude, Jennyen
dc.contributor.authorRudolph, Anjaen
dc.contributor.authorDevilee, Peteren
dc.contributor.authorSeynaeve, Carolineen
dc.contributor.authorHopper, John Len
dc.contributor.authorSouthey, Melissa Cen
dc.contributor.authorJohn, Esther Men
dc.contributor.authorWhittemore, Alice Sen
dc.contributor.authorBolla, Manjeet Ken
dc.contributor.authorWang, Jeanen
dc.contributor.authorMichailidou, Kyriakien
dc.contributor.authorDennis, Joeen
dc.contributor.authorEaston, Douglasen
dc.contributor.authorSchmidt, Marjanka Ken
dc.contributor.authorNevanlinna, Helien
dc.date.accessioned2016-09-21T12:55:14Z
dc.date.available2016-09-21T12:55:14Z
dc.date.issued2016-10-06en
dc.identifier.issn1098-3600
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/260281
dc.description.abstractPurpose: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC) Methods: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. Results: The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21–2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55–1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86–4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16–1.74), indicating a lifetime risk close to the population average. Conclusion: Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.
dc.description.sponsorshipUK funders include Cancer Research UK, Breakthrough Breast Cancer and NIHR. See article for full list of funders.
dc.languageEnglishen
dc.language.isoenen
dc.publisherNature Publishing Group
dc.subjectbreast canceren
dc.subjectCHEK2*1100delCen
dc.subjectpolygenic risk score (PRS)en
dc.subjectcommon variantsen
dc.subjectBreast Cancer Association Consortium (BCAC)en
dc.titleGenetic modifiers of CHEK2*1100delC-associated breast cancer risken
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/gim.2016.147en
prism.endingPage603
prism.publicationDate2016en
prism.publicationNameGenetics in Medicineen
prism.startingPage599
prism.volume19en
dc.identifier.doi10.17863/CAM.4512
dcterms.dateAccepted2016-07-27en
rioxxterms.versionofrecord10.1038/gim.2016.147en
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2016-10-06en
dc.contributor.orcidPharoah, Paul [0000-0001-8494-732X]
dc.contributor.orcidDunning, Alison [0000-0001-6651-7166]
dc.contributor.orcidLuben, Robert [0000-0002-5088-6343]
dc.contributor.orcidWang, Jean [0000-0002-9139-0627]
dc.contributor.orcidDennis, Joe [0000-0003-4591-1214]
dc.contributor.orcidEaston, Douglas [0000-0003-2444-3247]
dc.identifier.eissn1530-0366
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (16561)
pubs.funder-project-idNational Cancer Institute (NCI) (R01CA128978)
pubs.funder-project-idCancer Research UK (10124)
pubs.funder-project-idNational Cancer Institute (NCI) (U19CA148537)
pubs.funder-project-idNational Cancer Institute (NCI) (U19CA148065)


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