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    NPJ breast cancer. 2019 Nov 1. doi: 10.1038/s41523-019-0127-5. pii: 127. pmc: PMC6825205
    The :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.
    Figlioli G1,  Bogliolo M2,  Catucci I3,  Caleca L4,  Lasheras SV5,  Pujol R6,  Kiiski JI7,  Muranen TA8,  Barnes DR9,  Dennis J10,  Michailidou K11,  Bolla MK12,  Leslie G13,  Aalfs CM14,  Adank MA15,  Adlard J16,  Agata S17,  Cadoo K18,  Agnarsson BA19,  Ahearn T20,  Aittomäki K21,  Ambrosone CB22,  Andrews L23,  Anton-Culver H24,  Antonenkova NN25,  Arndt V26,  Arnold N27,  Aronson KJ28,  Arun BK29,  Asseryanis E30,  Auber B31,  Auvinen P32,  Azzollini J33,  Balmaña J34,  Barkardottir RB35,  Barrowdale D36,  Barwell J37,  Beane Freeman LE38,  Beauparlant CJ39,  Beckmann MW40,  Behrens S41,  Benitez J42,  Berger R43,  Bermisheva M44,  Blanco AM45,  Blomqvist C46,  Bogdanova NV47,  Bojesen A48,  Bojesen SE49,  Bonanni B50,  Borg A51,  Brady AF52,  Brauch H53,  Brenner H54,  Brüning T55,  Burwinkel B56,  Buys SS57,  Caldés T58,  Caliebe A59,  Caligo MA60,  Campa D61,  Campbell IG62,  Canzian F63,  Castelao JE64,  Chang-Claude J65,  Chanock SJ66,  Claes KBM67,  Clarke CL68,  Collavoli A69,  Conner TA70,  Cox DG71,  Cybulski C72,  Czene K73,  Daly MB74,  de la Hoya M75,  Devilee P76,  Diez O77,  Ding YC78,  Dite GS79,  Ditsch N80,  Domchek SM81,  Dorfling CM82,  Dos-Santos-Silva I83,  Durda K84,  Dwek M85,  Eccles DM86,  Ekici AB87,  Eliassen AH88,  Ellberg C89,  Eriksson M90,  Evans DG91,  Fasching PA92,  Figueroa J93,  Flyger H94,  Foulkes WD95,  Friebel TM96,  Friedman E97,  Gabrielson M98,  Gaddam P99,  Gago-Dominguez M100,  Gao C101,  Gapstur SM102,  Garber J103,  García-Closas M104,  García-Sáenz JA105,  Gaudet MM106,  Gayther SA107,  Giles GG108,  Glendon G109,  Godwin AK110,  Goldberg MS111,  Goldgar DE112,  Guénel P113,  Gutierrez-Barrera AM114,  Haeberle L115,  Haiman CA116,  Håkansson N117,  Hall P118,  Hamann U119,  Harrington PA120,  Hein A121,  Heyworth J122,  Hillemanns P123,  Hollestelle A124,  Hopper JL125,  Hosgood HD126,  Howell A127,  Hu C128,  Hulick PJ129,  Hunter DJ130,  Imyanitov EN131,  Isaacs C132,  Jakimovska M133,  Jakubowska A134,  James P135,  Janavicius R136,  Janni W137,  John EM138,  Jones ME139,  Jung A140,  Kaaks R141,  Karlan BY142,  Khusnutdinova E143,  Kitahara CM144,  Konstantopoulou I145,  Koutros S146,  Kraft P147,  Lambrechts D148,  Lazaro C149,  Le Marchand L150,  Lester J151,  Lesueur F152,  Lilyquist J153,  Loud JT154,  Lu KH155,  Luben RN156,  Lubinski J157,  Mannermaa A158,  Manoochehri M159,  Manoukian S160,  Margolin S161,  Martens JWM162,  Maurer T163,  Mavroudis D164,  Mebirouk N165,  Meindl A166,  Menon U167,  Miller A168,  Montagna M169,  Nathanson KL170,  Neuhausen SL171,  Newman WG172,  Nguyen-Dumont T173,  Nielsen FC174,  Nielsen S175,  Nikitina-Zake L176,  Offit K177,  Olah E178,  Olopade OI179,  Olshan AF180,  Olson JE181,  Olsson H182,  Osorio A183,  Ottini L184,  Peissel B185,  Peixoto A186,  Peto J187,  Plaseska-Karanfilska D188,  Pocza T189,  Presneau N190,  Pujana MA191,  Punie K192,  Rack B193,  Rantala J194,  Rashid MU195,  Rau-Murthy R196,  Rennert G197,  Lejbkowicz F198,  Rhenius V199,  Romero A200,  Rookus MA201,  Ross EA202,  Rossing M203,  Rudaitis V204,  Ruebner M205,  Saloustros E206,  Sanden K207,  Santamariña M208,  Scheuner MT209,  Schmutzler RK210,  Schneider M211,  Scott C212,  Senter L213,  Shah M214,  Sharma P215,  Shu XO216,  Simard J217,  Singer CF218,  Sohn C219,  Soucy P220,  Southey MC221,  Spinelli JJ222,  Steele L223,  Stoppa-Lyonnet D224,  Tapper WJ225,  Teixeira MR226,  Terry MB227,  Thomassen M228,  Thompson J229,  Thull DL230,  Tischkowitz M231,  Tollenaar RAEM232,  Torres D233,  Troester MA234,  Truong T235,  Tung N236,  Untch M237,  Vachon CM238,  van Rensburg EJ239,  van Veen EM240,  Vega A241,  Viel A242,  Wappenschmidt B243,  Weitzel JN244,  Wendt C245,  Wieme G246,  Wolk A247,  Yang XR248,  Zheng W249,  Ziogas A250,  Zorn KK251,  Dunning AM252,  Lush M253,  Wang Q254,  McGuffog L255,  Parsons MT256,  Pharoah PDP257,  Fostira F258,  Toland AE259,  Andrulis IL260,  Ramus SJ261,  Swerdlow AJ262,  Greene MH263,  Chung WK264,  Milne RL265,  Chenevix-Trench G266,  Dörk T267,  Schmidt MK268,  Easton DF269,  Radice P270,  Hahnen E271,  Antoniou AC272,  Couch FJ273,  Nevanlinna H274,  Surrallés J275,  Peterlongo P276
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    Abstract

    Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes , , , , and are associated with breast cancer risk. , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of or . These three variants were also studied functionally by measuring survival and chromosome fragility in patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44,  = 0.034 and OR = 3.79;  = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for :p.Arg658* and found that also :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96;  = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat -associated tumors.


    © The Author(s) 2019.

    KEYWORDS: Cancer genetics

    Publikations ID: 31700994
    Quelle: öffnen
     
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