Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. A Osorio1, R L Milne2, G Pita3, P Peterlongo4,5, T Heikkinen6, J Simard7, G Chenevix-Trench8, A B Spurdle8, J Beesley8, X Chen8, S Healey8, KConFab9, S L Neuhausen10, Y C Ding10, F J Couch11,12, X Wang11, N Lindor13, S Manoukian4, M Barile14, A Viel15, L Tizzoni5,16, C I Szabo17, L Foretova18, M Zikan19, K Claes20, M H Greene21, P Mai21, G Rennert22, F Lejbkowicz22, O Barnett-Griness22, I L Andrulis23,24, H Ozcelik24, N Weerasooriya23, OCGN23, A-M Gerdes25, M Thomassen25, D G Cruger26, M A Caligo27, E Friedman28,29, B Kaufman28,29, Y Laitman28, S Cohen28, T Kontorovich28, R Gershoni-Baruch30, E Dagan31,32, H Jernström33, M S Askmalm34, B Arver35, B Malmer36, SWE-BRCA37, S M Domchek38, K L Nathanson38, J Brunet39, T Ramón y Cajal40, D Yannoukakos41, U Hamann42, HEBON37, F B L Hogervorst43, S Verhoef43, EB Gómez García44,45, J T Wijnen46,47, A van den Ouweland48, EMBRACE37, D F Easton49, S Peock49, M Cook49, C T Oliver49, D Frost49, C Luccarini50, D G Evans51, F Lalloo51, R Eeles52, G Pichert53, J Cook54, S Hodgson55, P J Morrison56, F Douglas57, A K Godwin58, GEMO59,60,61, O M Sinilnikova59,60, L Barjhoux59,60, D Stoppa-Lyonnet61, V Moncoutier61, S Giraud59, C Cassini62,63, L Olivier-Faivre62,63, F Révillion64, J-P Peyrat64, D Muller65, J-P Fricker65, H T Lynch66, E M John67, S Buys68, M Daly69, J L Hopper70, M B Terry71, A Miron72, Y Yassin72, D Goldgar73, Breast Cancer Family Registry37, C F Singer74, D Gschwantler-Kaulich74, G Pfeiler74, A-C Spiess74, Thomas v O Hansen75, O T Johannsson76, T Kirchhoff77, K Offit77, K Kosarin77, M Piedmonte78, G C Rodriguez79, K Wakeley80, J F Boggess81, J Basil82, P E Schwartz83, S V Blank84, A E Toland85, M Montagna86, C Casella87, E N Imyanitov88, A Allavena89, R K Schmutzler90, B Versmold90, C Engel91, A Meindl92, N Ditsch93, N Arnold94, D Niederacher95, H Deißler96, B Fiebig97, R Varon-Mateeva98, D Schaefer99, U G Froster100, T Caldes101, M de la Hoya101, L McGuffog49, A C Antoniou49, H Nevanlinna6, P Radice4,5 and J Benítez1,3 on behalf of CIMB

A monotonicity formula for minimal sets with a sliding boundary condition

We prove a monotonicity formula for minimal or almost minimal sets for the Hausdorff measure $\cal{H}^d$, subject to a sliding boundary constraint where competitors for $E$ are obtained by deforming $E$ by a one-parameter family of functions $\varphi_t$ such that $\varphi_t(x) \in L$ when $x\in E$ lies on the boundary $L$. In the simple case when $L$ is an affine subspace of dimension $d-1$, the monotone or almost monotone functional is given by $F(r) = r^{-d} \cal{H}^d(E \cap B(x,r)) + r^{-d} \cal{H}^d(S \cap B(x,r))$, where $x$ is any point of $E$ (not necessarily on $L$) and $S$ is the shade of $L$ with a light at $x$. We then use this, the description of the case when $F$ is constant, and a limiting argument, to give a rough description of $E$ near $L$ in two simple cases. ----- On donne une formule de monotonie pour des ensembles minimaux ou presque minimaux pour la mesure de Hausdorff $\cal{H}^d$, avec une condition de bord o\`u les comp\'etiteurs de $E$ sont obtenus en d\'eformant $E$ par une famille \`a un param\`etre de fonctions $\varphi_t$ telles que $\varphi_t(x)\in L$ quand $x\in E$ se trouve sur la fronti\`ere $L$. Dans le cas simple o\`u $L$ est un sous-espace affine de dimension $d-1$, la fonctionelle monotone ou presque monotone est donn\'ee par $F(r) = r^{-d} \cal{H}^d(E \cap B(x,r)) + r^{-d} \cal{H}^d(S \cap B(x,r))$, o\`u $x$ est un point de $E$, pas forc\'ement dans $L$, et $S$ est l'ombre de $L$, \'eclair\'ee depuis $x$. On utilise ceci, la description des cas o\`u $F$ est constante, et un argument de limite, pour donner une description de $E$ pr\`es de $L$ dans deux cas simples.Comment: 100 page