title: BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.
abstract: BACKGROUND
  The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.
  
  
  METHODS
  Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided.
  
  
  RESULTS
  The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed.
  
  
  CONCLUSIONS
  Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
authors.forename: Huong D
authors.initials: HD
authors.lastname: Meeks
authors.forename: Honglin
authors.initials: H
authors.lastname: Song
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Michailidou
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Bolla
authors.forename: Joe
authors.initials: J
authors.lastname: Dennis
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Daniel
authors.initials: D
authors.lastname: Barrowdale
authors.forename: Debra
authors.initials: D
authors.lastname: Frost
authors.forename: Lesley
authors.initials: L
authors.lastname: McGuffog
authors.forename: Steve
authors.initials: S
authors.lastname: Ellis
authors.forename: Bingjian
authors.initials: B
authors.lastname: Feng
authors.forename: Saundra S
authors.initials: SS
authors.lastname: Buys
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: Andrea
authors.initials: A
authors.lastname: Tesoriero
authors.forename: Paul A
authors.initials: PA
authors.lastname: James
authors.forename: Fiona
authors.initials: F
authors.lastname: Bruinsma
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
authors.forename: Frans B L
authors.initials: FB
authors.lastname: Hogervorst
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckman
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.forename: Olivia
authors.initials: O
authors.lastname: Fletcher
authors.forename: Nichola
authors.initials: N
authors.lastname: Johnson
authors.forename: Elinor J
authors.initials: EJ
authors.lastname: Sawyer
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Susana
authors.initials: S
authors.lastname: Banerjee
authors.forename: Usha
authors.initials: U
authors.lastname: Menon
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.forename: Frederik
authors.initials: F
authors.lastname: Marme
authors.forename: Anja
authors.initials: A
authors.lastname: Rudolph
authors.forename: Ramunas
authors.initials: R
authors.lastname: Janavicius
authors.forename: Laima
authors.initials: L
authors.lastname: Tihomirova
authors.forename: Nadine
authors.initials: N
authors.lastname: Tung
authors.forename: Judy
authors.initials: J
authors.lastname: Garber
authors.forename: Daniel
authors.initials: D
authors.lastname: Cramer
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Terry
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Poole
authors.forename: Shelley S
authors.initials: SS
authors.lastname: Tworoger
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Dorfling
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: van Rensburg
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Pascal
authors.initials: P
authors.lastname: Guénel
authors.forename: Thérèse
authors.initials: T
authors.lastname: Truong
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: Francesca
authors.initials: F
authors.lastname: Damiola
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mazoyer
authors.forename: Olga M
authors.initials: OM
authors.lastname: Sinilnikova
authors.forename: Claudine
authors.initials: C
authors.lastname: Isaacs
authors.forename: Christine
authors.initials: C
authors.lastname: Maugard
authors.forename: Stig E
authors.initials: SE
authors.lastname: Bojesen
authors.forename: Henrik
authors.initials: H
authors.lastname: Flyger
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Gerdes
authors.forename: Thomas V O
authors.initials: TV
authors.lastname: Hansen
authors.forename: Allen
authors.initials: A
authors.lastname: Jensen
authors.forename: Susanne K
authors.initials: SK
authors.lastname: Kjaer
authors.forename: Claus
authors.initials: C
authors.lastname: Hogdall
authors.forename: Estrid
authors.initials: E
authors.lastname: Hogdall
authors.forename: Inge Sokilde
authors.initials: IS
authors.lastname: Pedersen
authors.forename: Mads
authors.initials: M
authors.lastname: Thomassen
authors.forename: Javier
authors.initials: J
authors.lastname: Benitez
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.forename: Miguel de la
authors.initials: Mde L
authors.lastname: Hoya
authors.forename: Pedro Perez
authors.initials: PP
authors.lastname: Segura
authors.forename: Orland
authors.initials: O
authors.lastname: Diez
authors.forename: Conxi
authors.initials: C
authors.lastname: Lazaro
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.forename: Lee
authors.initials: L
authors.lastname: Eunjung
authors.forename: Esther M
authors.initials: EM
authors.lastname: John
authors.forename: Susan L
authors.initials: SL
authors.lastname: Neuhausen
authors.forename: Yuan Chun
authors.initials: YC
authors.lastname: Ding
authors.forename: Danielle
authors.initials: D
authors.lastname: Castillo
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weitzel
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Ganz
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nussbaum
authors.forename: Salina B
authors.initials: SB
authors.lastname: Chan
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.forename: Jenny
authors.initials: J
authors.lastname: Lester
authors.forename: Anna
authors.initials: A
authors.lastname: Wu
authors.forename: Simon
authors.initials: S
authors.lastname: Gayther
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.forename: Weiva
authors.initials: W
authors.lastname: Sieh
authors.forename: Alice S
authors.initials: AS
authors.lastname: Whittermore
authors.forename: Alvaro N A
authors.initials: AN
authors.lastname: Monteiro
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Phelan
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Terry
authors.forename: Marion
authors.initials: M
authors.lastname: Piedmonte
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Mark
authors.initials: M
authors.lastname: Robson
authors.forename: Douglas
authors.initials: D
authors.lastname: Levine
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Moysich
authors.forename: Rikki
authors.initials: R
authors.lastname: Cannioto
authors.forename: Sara H
authors.initials: SH
authors.lastname: Olson
authors.forename: Mary B
authors.initials: MB
authors.lastname: Daly
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Susan M
authors.initials: SM
authors.lastname: Domchek
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
authors.forename: Dong
authors.initials: D
authors.lastname: Liang
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrant
authors.forename: Roberta
authors.initials: R
authors.lastname: Ness
authors.forename: Francesmary
authors.initials: F
authors.lastname: Modugno
authors.forename: Leigh
authors.initials: L
authors.lastname: Pearce
authors.forename: Marc T
authors.initials: MT
authors.lastname: Goodman
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Thompson
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Katja
authors.initials: K
authors.lastname: Butterbach
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Eric
authors.initials: E
authors.lastname: Hahnen
authors.forename: Barbara
authors.initials: B
authors.lastname: Wappenschmidt
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.forename: Thomas
authors.initials: T
authors.lastname: Brüning
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Sofia
authors.initials: S
authors.lastname: Khan
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Liisa M
authors.initials: LM
authors.lastname: Pelttari
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Ralf
authors.initials: R
authors.lastname: Butzow
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Bogdanova
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.forename: Sara
authors.initials: S
authors.lastname: Margolin
authors.forename: Johanna
authors.initials: J
authors.lastname: Rantala
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.forename: Kathleen B M
authors.initials: KB
authors.lastname: Claes
authors.forename: Tom Van
authors.initials: TV
authors.lastname: Maerken
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: Dieter
authors.initials: D
authors.lastname: Flesch-Janys
authors.forename: Florian
authors.initials: F
authors.lastname: Heitz
authors.forename: Raymonda
authors.initials: R
authors.lastname: Varon-Mateeva
authors.forename: Paolo
authors.initials: P
authors.lastname: Peterlongo
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.forename: Alessandra
authors.initials: A
authors.lastname: Viel
authors.forename: Monica
authors.initials: M
authors.lastname: Barile
authors.forename: Bernard
authors.initials: B
authors.lastname: Peissel
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.forename: Marco
authors.initials: M
authors.lastname: Montagna
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliani
authors.forename: Ana
authors.initials: A
authors.lastname: Peixoto
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.forename: Anita
authors.initials: A
authors.lastname: Collavoli
authors.forename: Emily
authors.initials: E
authors.lastname: Hallberg
authors.forename: Janet E
authors.initials: JE
authors.lastname: Olson
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hart
authors.forename: Hermela
authors.initials: H
authors.lastname: Shimelis
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.forename: Sue
authors.initials: S
authors.lastname: Healey
authors.forename: Kathy
authors.initials: K
authors.lastname: Tucker
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Mark S
authors.initials: MS
authors.lastname: Goldberg
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.forename: Jacques
authors.initials: J
authors.lastname: Simard
authors.forename: Penny
authors.initials: P
authors.lastname: Soucy
authors.forename: Diana M
authors.initials: DM
authors.lastname: Eccles
authors.forename: Nhu
authors.initials: N
authors.lastname: Le
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Borresen-Dale
authors.forename: Vessela
authors.initials: V
authors.lastname: Kristensen
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.forename: Line
authors.initials: L
authors.lastname: Bjorge
authors.forename: Elisa V
authors.initials: EV
authors.lastname: Bandera
authors.forename: Harvey
authors.initials: H
authors.lastname: Risch
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Alicia
authors.initials: A
authors.lastname: Beeghly-Fadiel
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
authors.forename: Robert A E M
authors.initials: RA
authors.lastname: Tollenaar
authors.forename: Ans M W van der
authors.initials: AM
authors.lastname: Ouweland
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: Julia A
authors.initials: JA
authors.lastname: Knight
authors.forename: Steven
authors.initials: S
authors.lastname: Narod
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
authors.forename: Jonine
authors.initials: J
authors.lastname: Figueroa
authors.forename: Mark H
authors.initials: MH
authors.lastname: Greene
authors.forename: Phuong L
authors.initials: PL
authors.lastname: Mai
authors.forename: Jennifer T
authors.initials: JT
authors.lastname: Loud
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Closas
authors.forename: Minouk J
authors.initials: MJ
authors.lastname: Schoemaker
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.forename: Hatef
authors.initials: H
authors.lastname: Darabi
authors.forename: Iain
authors.initials: I
authors.lastname: McNeish
authors.forename: Nadeem
authors.initials: N
authors.lastname: Siddiquil
authors.forename: Rosalind
authors.initials: R
authors.lastname: Glasspool
authors.forename: Ava
authors.initials: A
authors.lastname: Kwong
authors.forename: Sue K
authors.initials: SK
authors.lastname: Park
authors.forename: Soo Hwang
authors.initials: SH
authors.lastname: Teo
authors.forename: Sook-Yee
authors.initials: SY
authors.lastname: Yoon
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.forename: Satoyo
authors.initials: S
authors.lastname: Hosono
authors.forename: Yin Ling
authors.initials: YL
authors.lastname: Woo
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Gao
authors.forename: Lenka
authors.initials: L
authors.lastname: Foretova
authors.forename: Christian F
authors.initials: CF
authors.lastname: Singer
authors.forename: Christine
authors.initials: C
authors.lastname: Rappaport-Feurhauser
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.forename: Yael
authors.initials: Y
authors.lastname: Laitman
authors.forename: Gad
authors.initials: G
authors.lastname: Rennert
authors.forename: Evgeny N
authors.initials: EN
authors.lastname: Imyanitov
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hulick
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.forename: Leigha
authors.initials: L
authors.lastname: Senter
authors.forename: Edith
authors.initials: E
authors.lastname: Olah
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doherty
authors.forename: Joellen
authors.initials: J
authors.lastname: Schildkraut
authors.forename: Linetta B
authors.initials: LB
authors.lastname: Koppert
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Leon F A G
authors.initials: LF
authors.lastname: Massuger
authors.forename: Linda S
authors.initials: LS
authors.lastname: Cook
authors.forename: Tanja
authors.initials: T
authors.lastname: Pejovic
authors.forename: Jingmei
authors.initials: J
authors.lastname: Li
authors.forename: Ake
authors.initials: A
authors.lastname: Borg
authors.forename: Anna
authors.initials: A
authors.lastname: Öfverholm
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Rossing
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.forename: Karin
authors.initials: K
authors.lastname: Henriksson
authors.forename: Angela
authors.initials: A
authors.lastname: Cox
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Pasini
authors.forename: Mitul
authors.initials: M
authors.lastname: Shah
authors.forename: Maria
authors.initials: M
authors.lastname: Kabisch
authors.forename: Diana
authors.initials: D
authors.lastname: Torres
authors.forename: Anna
authors.initials: A
authors.lastname: Jakubowska
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.forename: Jacek
authors.initials: J
authors.lastname: Gronwald
authors.forename: Bjarni A
authors.initials: BA
authors.lastname: Agnarsson
authors.forename: Jolanta
authors.initials: J
authors.lastname: Kupryjanczyk
authors.forename: Joanna
authors.initials: J
authors.lastname: Moes-Sosnowska
authors.forename: Florentia
authors.initials: F
authors.lastname: Fostira
authors.forename: Irene
authors.initials: I
authors.lastname: Konstantopoulou
authors.forename: Susan
authors.initials: S
authors.lastname: Slager
authors.forename: Michael
authors.initials: M
authors.lastname: Jones
authors.forename: Antonis C
authors.initials: AC
authors.lastname: Antoniou
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.forename: Anthony
authors.initials: A
authors.lastname: Swerdlow
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
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authors.forename: Per
authors.initials: P
authors.lastname: Hall
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authors.lastname: Easton
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
mesh_terms: D000328:Adult; D000368:Aged; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D018388:Codon, Terminator; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D016015:Logistic Models; D008239:Lysine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D018388:Codon, Terminator; D008239:Lysine