A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer

被引：379

作者：

Polak, Paz ^{[1
,2
,3
]}

Kim, Jaegil ^{[1
]}

Braunstein, Lior Z. ^{[1
,4
]}

Karlic, Rosa ^{[5
]}

Haradhavala, Nicholas J. ^{[1
,2
]}

Tiao, Grace ^{[1
]}

Rosebrock, Daniel ^{[1
]}

Livitz, Dimitri ^{[1
]}

Kubler, Kirsten ^{[1
,2
,3
]}

Mouw, Kent W. ^{[3
,6
,7
]}

Kamburov, Atanas ^{[1
,2
,3
]}

Maruvka, Yosef E. ^{[1
,2
,3
]}

Leshchiner, Ignaty ^{[1
]}

Lander, Eric S. ^{[1
,8
,9
]}

Golub, Todd R. ^{[1
,3
,10
,11
,12
]}

Zick, Aviad ^{[13
]}

Orthwein, Alexandre ^{[14
]}

Lawrence, Michael S. ^{[1
,2
]}

Batra, Rajbir N. ^{[15
,16
,17
]}

Caldas, Carlos ^{[15
,16
,17
]}

Haber, Daniel A. ^{[2
,3
]}

Laird, Peter W. ^{[18
]}

Shen, Hui ^{[18
]}

Ellisen, Leif W. ^{[2
,3
]}

D'Andrea, Alan D. ^{[19
,20
]}

Chanock, Stephen J. ^{[21
]}

Foulkes, William D. ^{[14
,22
,23
]}

Getz, Gad ^{[1
,2
,3
,24
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[2] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA

[3] Harvard Med Sch, Boston, MA 02115 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA

[5] Univ Zagreb, Div Mol Biol, Dept Biol, Bioinformat Grp,Fac Sci, Zagreb, Croatia

[6] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA

[7] Dana Farber Canc Inst, Boston, MA 02115 USA

[8] MIT, Dept Biol, Cambridge, MA USA

[9] Harvard Med Sch, Dept Syst Biol, Boston, MA USA

[10] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[11] Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA

[12] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[13] Hadassah Hebrew Univ, Dept Oncol, Med Ctr, Jerusalem, Israel

[14] McGill Univ, Dept Oncol, Montreal, PQ, Canada

[15] Univ Cambridge, Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Cambridge, England

[16] Canc Res UK Cambridge Ctr, Cambridge, England

[17] Univ Cambridge, Dept Oncol, Hutchison MRC Res Ctr, Cambridge Biomed Campus, Cambridge, England

[18] Van Andel Res Inst, Grand Rapids, MI USA

[19] Dana Farber Canc Inst, Ctr DNA Damage & Repair, Boston, MA 02115 USA

[20] Harvard Med Sch, Ludwig Ctr, Harvard, Boston, MA USA

[21] US Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA

[22] McGill Univ, Lady Davis Inst Med Res, Dept Human Genet, Montreal, PQ, Canada

[23] McGill Univ, Res Inst, Hlth Ctr, Montreal, PQ, Canada

[24] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

来源：

NATURE GENETICS | 2017年 / 49卷 / 10期

关键词：

COMPREHENSIVE MOLECULAR PORTRAITS; GERMLINE BRCA1 MUTATIONS; OVARIAN-CANCER; SEQUENCE VARIATION; PARP INHIBITORS; FAMILY-HISTORY; TUMORS; LANDSCAPE; VARIANTS; SUSCEPTIBILITY;

D O I：

10.1038/ng.3934

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing similar to 1,000 breast cancer samples, we confirmed this association and established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.

引用

页码：1476 / +

页数：13

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