Abstract
background We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (r1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (oC). this study aimed to assess these cancer risks for r1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*r1699Q carriers. Methods Data were collected from 129 BRCA1*r1699Q families ascertained internationally by eNIGMA (evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and oC risks. relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. results In this cohort the cumulative risk of BC and oC by age 70 years was 20% and 6%, respectively. the relative risk for developing cancer was higher when using a model that included the effects of both the r1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for oC 6.41 vs 5.83). Conclusion our results confirm that BRCA1*r1699Q confers an intermediate risk for BC and oC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 15-20 |
| Number of pages | 6 |
| Journal | Journal of medical genetics |
| Volume | 55 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2018 |
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
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In: Journal of medical genetics, Vol. 55, No. 1, 01.2018, p. 15-20.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant
T2 - Breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium
AU - Moghadasi, Setareh
AU - Meeks, Huong D.
AU - Vreeswijk, Pg Maaike
AU - Janssen, Linda A.M.
AU - Borg, Åke
AU - Ehrencrona, Hans
AU - Paulsson-Karlsson, Ylva
AU - Wappenschmidt, Barbara
AU - Engel, Christoph
AU - Gehrig, Andrea
AU - Arnold, Norbert
AU - Van Overeem Hansen, Thomas
AU - Thomassen, Mads
AU - Jensen, Uffe Birk
AU - Kruse, Torben A.
AU - Ejlertsen, Bent
AU - Gerdes, Anne Marie
AU - Pedersen, Inge Søkilde
AU - Caputo, Sandrine M.
AU - Couch, Fergus
AU - Hallberg, Emily J.
AU - Van Den Ouweland, Ans M.W.
AU - Collée, Margriet J.
AU - Teugels, Erik
AU - Adank, Muriel A.
AU - Van Der Luijt, Rob B.
AU - Mensenkamp, R. Arjen
AU - Oosterwijk, Jan C.
AU - Blok, Marinus J.
AU - Janin, Nicolas
AU - Claes, Kathleen B.M.
AU - Tucker, Kathy
AU - Viassolo, Valeria
AU - Toland, Amanda Ewart
AU - Eccles, Diana E.
AU - Devilee, Peter
AU - Van Asperen, Christie J.
AU - Spurdle, Amanda B.
AU - Goldgar, David E.
AU - García, Encarna Gómez
N1 - Funding Information: Acknowledgements We thank the many families who participated in this study. this work is supported by the efforts of laboratory and clinical staff from many centres around the world. In particular, we would like to acknowledge all members of the eNIGMA consortium who contributed to discussions about clinical management of variant carriers, members of the GC-hBoC (German Consortium of hereditary Breast and ovarian Cancer), members of the kConFab (Kathleen Cuningham Foundation Consortium for research into Familial Breast Cancer),and the members of these consortia: LoB Dutch Belgian Consortium: r Blok, D Bodmer, p Bouwman, K Claes, S Debrake, A Gheldof, J J p Gille, e Gomez Garcia, F hogervorst, A h van der hout, L van de kolk, M J Koudijs, r B van der Luijt, A Mensenkamp, G Michils, S Moghadasi, p Nederlof, A van den ouweland, e roisenberg, K Segers, N van der Stoep, K Storm, S Seneca, e teugels, C M tops, M Vogel, M p G Vreeswijk, J t Wijnen, S Willocx; SWe-BrCA, the Swedish BrCA1 and BrCA2 Study Collaborators: Gothenburg, Sahlgrenska University hospital: Zakaria einbeigi; Linköping University hospital: Marie Stenmark-Askmalm; Lund University hospital: hans ehrencrona, therese törngren, Anders Kvist, Åke Borg; Stockholm, Karolinska University hospital: Brita Arver, Annika Lindblom, emma tham; Umeå University hospital: Beatrice Melin; Uppsala University hospital: Ylva paulsson-Karlsson; French CoVAr group collaborators: M Mathieu-Dramard: ChU Amiens, Amiens; o Ingster: Centre paul papin, Angers; p Gesta: Centre hospitalier d’Angoulême, Angoulème; h Dreyfus: Institut Sainte-Catherine, Avignon; M A Collonge-rame, J L Bresson, C populaire: ChU Besançon, Besançon; M Longy; e Barouk-Simonet, V Bubien; N Sévenet, F Bonnet, N Jones: Institut Bergonié, Bordeaux; I Mortemousque: Ch Jacques Cœur, Bourges; S Audebert-Bellanger: ChU de Brest, Brest; pascaline B; A hardouin, D Vaur, S Krieger, L Castéra: Centre François Baclesse, Caen; S Ferrer: Centre hospitalier hôtel Dieu, Chambery; N Uhrhammer, Y J Bignon: Centre Jean perrin, Clermont-Ferrand; L Faivre-olivier, S el Chehadeh; S Lizard: ChU de Dijon, Dijon; o Béra: ChU de Fort de France, Martinique; D Leroux, h Dreyfus, A Béchet: ChU de Grenoble, Grenoble; h ranjatoelina: ChU Sud réunion, La réunion; V Layet: hôpital Flaubert, Le havre; C Adenis; J-p peyrat, F revillion: Centre oscar Lambret, Lille; S Lejeune, S Manouvrier-hanu: ChrU Lille, Lille; L Vénat-Bouvet: ChU Dupuytren, Limoges; C Lasset, V Bonadona; S Mazoyer; o Sininilkova, M Léone, N Boutry-Kryza: Centre Léon Bérard, Lyon; S Giraud: hospices Civils de Lyon, Lyon; h Sobol, t Noguchi, V Bourdon, A remenieras, F eisinger: Institut paoli-Calmettes, Marseille; h Zattara: ChU La timone, Marseille; I Coupier; J-M rey, p-o harmand: ChU Arnaud de Villeneuve, Montpelier; e Luporsi: Centre Alexis Vautrin, Nancy; M Bronner, J Sokolowska-Gillois, p Jonveaux, C philippe: ChU Nancy, Nancy; C Delnatte, V Guibert, S Bézieau, e Cauchin: Centre rené Gauducheau, Nantes; A Lortholary: Centre Catherine de Sienne, Nantes; V Mari; M Frenay: Centre AntoineLacassagne, Nice; J Chiesa: ChrU Caremeau, Nîmes; e rouleau, C Lefol, r Lidereau; V Caux-Moncoutier, L Golmard, C houdayer, B Buecher, M Gauthier-Villars, M Belotti, A Depauw, S Demontety, D Stoppa-Lyonnet: Institut Curie, paris; F Coulet, F Soubrier, C Colas, A Fajac, M Warcoin: Groupe hospitalier pitié-Salpêtrière, paris; p-L puig-heGp, paris; M Lackmy-port-Lis: ChU de pointe à pitre, Guadeloupe; A Marie Savoye; C Delvincourt, o Beaudoux: Institut Jean Godinot, reims; Dominique Gaillard; C poirsier; M Mozelle-Nivoix: ChU de reims, reims; C Dugast; C Abadie: Centre eugène Marquis, rennes; t Frebourg, J tinat, A rossi, I thevenet: ChU de rouen, rouen; F prieur; M Lebrun: ChU Saint-etienne, Saint-etienne; C Noguès, e Fourme, C Sénéchal, A-M Birot, t Kogut-Kubiak: Institut Curie, Saint-Cloud; J-p Fricker, h Nehme-Schuster; D Muller, J Abecassis: Centre paul Strauss, Strasbourg; C Maugard: hopital Universitaire de Strasbourg, Strasbourg; L Gladieff; V Feillel; C toulas: Institut Claudius regaud, toulouse; M Mozelle: ChG troyes, troyes; o Caron; M Guillaud-Bataille, B Bressac-De paillerets: Institute Gustave roussy, Villejuif. We wish to thank heather thorne, eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NhMrC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National health and Medical research Council (NhMrC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, tasmania and South Australia, and the Cancer Foundation of Western Australia. Funding Information: Competing interests eGG has received an honorarium in the past 3 years from AstraZeneca for giving a course and a lecture. he (or rather, his department with him as primary contact) has received funding from Novartis oncology (unrestricted grant) and AstraZeneca (invited speaker). Kt has received an honorarium for chairing a mainstreaming genetic testing subcommittee and day seminar for AstraZeneca. Aet declares to have received an honorarium from American Cancer Society for grant review, NIh NCI pDQ as editorial board, Italian Ministry of health for grant review. Dee receives an honorarium from AstraZeneca via a contract with the university to provide consultancy advice from time to time (one or two advisory boards each year on average at the moment). DeG has received royalties from patents on the BrCA1 and BrCA2 genes from the University of Utah that are licensed to Myriad Genetics. All the other authors declare to have no conflicts of interest. Funding Information: the Netherlands organization for Scientific research (NWo), research program Mosaic (Grant 017.008.022); Van de Kampfonds from Leiden University Medical Centre (Grant 30.925). ABS is supported by an Australian NhMrC Senior research Fellowship. SMC was supported by the French National Cancer Institute (INCa). Funding Information: Funding the Netherlands organization for Scientific research (NWo), research program Mosaic (Grant 017.008.022); Van de Kampfonds from Leiden University Medical Centre (Grant 30.925). ABS is supported by an Australian NhMrC Senior research Fellowship. SMC was supported by the French National Cancer Institute (INCa). Publisher Copyright: © Article author(s).
PY - 2018/1
Y1 - 2018/1
N2 - background We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (r1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (oC). this study aimed to assess these cancer risks for r1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*r1699Q carriers. Methods Data were collected from 129 BRCA1*r1699Q families ascertained internationally by eNIGMA (evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and oC risks. relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. results In this cohort the cumulative risk of BC and oC by age 70 years was 20% and 6%, respectively. the relative risk for developing cancer was higher when using a model that included the effects of both the r1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for oC 6.41 vs 5.83). Conclusion our results confirm that BRCA1*r1699Q confers an intermediate risk for BC and oC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.
AB - background We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (r1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (oC). this study aimed to assess these cancer risks for r1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*r1699Q carriers. Methods Data were collected from 129 BRCA1*r1699Q families ascertained internationally by eNIGMA (evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and oC risks. relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. results In this cohort the cumulative risk of BC and oC by age 70 years was 20% and 6%, respectively. the relative risk for developing cancer was higher when using a model that included the effects of both the r1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for oC 6.41 vs 5.83). Conclusion our results confirm that BRCA1*r1699Q confers an intermediate risk for BC and oC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.
UR - http://www.scopus.com/inward/record.url?scp=85027525900&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85027525900&partnerID=8YFLogxK
U2 - 10.1136/jmedgenet-2017-104560
DO - 10.1136/jmedgenet-2017-104560
M3 - Article
C2 - 28490613
AN - SCOPUS:85027525900
SN - 0022-2593
VL - 55
SP - 15
EP - 20
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 1
ER -