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2015 ; 10
(4
): e0120020
Nephropedia Template TP
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Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and
breast cancer risk in BRCA1/2 mutation carriers
#MMPMID25830658
Blanco I
; Kuchenbaecker K
; Cuadras D
; Wang X
; Barrowdale D
; de Garibay GR
; Librado P
; Sánchez-Gracia A
; Rozas J
; Bonifaci N
; McGuffog L
; Pankratz VS
; Islam A
; Mateo F
; Berenguer A
; Petit A
; Català I
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; Tornero E
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; Nevanlinna H
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; Toland AE
; Karlan BY
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; Greene MH
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; Nussbaum RL
; Andrulis IL
; Domchek SM
; Nathanson KL
; Rebbeck TR
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; Jakubowska A
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; Claes K
; Van Maerken T
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; Hansen TV
; Jønson L
; Gerdes AM
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; de la Hoya M
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; Devilee P
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; Meijers-Heijboer HE
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; Aalfs CM
; Rodriguez GC
; Phillips KA
; Piedmonte M
; Nerenstone SR
; Bae-Jump VL
; O'Malley DM
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; Schmutzler RK
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PLoS One
2015[]; 10
(4
): e0120020
PMID25830658
show ga
While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary
epithelial polarization, common genetic variation in HMMR (gene product RHAMM)
may be associated with risk of breast cancer in BRCA1 mutation carriers.
Following on these observations, we further assessed the link between the
AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or
BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were
genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently
analyzed using a retrospective likelihood approach. The association of HMMR
rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed:
per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p =
1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1,
located next to AURKA, was also found to be associated with breast cancer risk in
BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p =
0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided
suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the
multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1
rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these
suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors
was found to potentially interact, influencing patients' survival. Together, the
results of this study support the hypothesis of a causative link between altered
function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation
carriers.