NAD(P)H:quinone oxidoreductase 1 NQO1☆2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer

被引：184

作者：

Fagerholm, Rainer ^{[3
]}

Hofstetter, Barbara ^{[1
,2
]}

Tommiska, Johanna ^{[3
]}

Aaltonen, Kirsimari ^{[3
,4
]}

Vrtel, Radek ^{[1
,2
,19
]}

Syrjakoski, Kirsi ^{[5
,6
]}

Kallioniemi, Anne ^{[5
,6
]}

Kilpivaara, Outi ^{[3
]}

Mannermaa, Arto ^{[7
,8
]}

Kosma, Veli-Matti ^{[7
,8
]}

Uusitupa, Matti ^{[9
]}

Eskelinen, Matti ^{[10
]}

Kataja, Vesa ^{[11
,12
]}

Aittomakii, Kristiina ^{[13
]}

von Smitten, Karl ^{[14
]}

Heikkilae, Paeivi ^{[15
]}

Lukas, Jiri ^{[1
,2
]}

Holli, Kaija ^{[16
,17
]}

Bartkova, Jirina ^{[1
,2
]}

Blomqvist, Carl ^{[18
]}

Bartek, Jiri ^{[1
,2
,19
]}

Nevanlinna, Heli ^{[3
]}

机构：

[1] Danish Canc Soc, Inst Canc Biol, DK-2100 Copenhagen, Denmark

[2] Danish Canc Soc, Ctr Genotox Stress Res, DK-2100 Copenhagen, Denmark

[3] Univ Helsinki, Cent Hosp, Dept Obstet & Ginecol, FI-00029 Helsinki, Finland

[4] Univ Helsinki, Cent Hosp, Dept Oncol, FI-00029 Helsinki, Finland

[5] Univ Tampere, Inst Med Technol, FI-33014 Tampere, Finland

[6] Univ Tampere, Tampere Univ Hosp, Canc Genet Lab, FI-33014 Tampere, Finland

[7] Univ Kuopio, Inst Clin Med Pathol & Forens Med, FI-70211 Kuopio, Finland

[8] Kuopio Univ Hosp, Dept Pathol, FI-70211 Kuopio, Finland

[9] Kuopio Univ Hosp, Dept Publ Hlth & Clin Nutr, FI-70211 Kuopio, Finland

[10] Kuopio Univ Hosp, Dept Surg, FI-70211 Kuopio, Finland

[11] Kuopio Univ Hosp, Dept Oncol, FI-70211 Kuopio, Finland

[12] Vaasa Cent Hosp, Dept Oncol, FI-651000 Vaasa, Finland

[13] Univ Helsinki, Cent Hosp, Dept Clin Genet, FI-00029 Helsinki, Finland

[14] Univ Helsinki, Cent Hosp, Dept Surg, FI-00029 Helsinki, Finland

[15] Univ Helsinki, Cent Hosp, Dept Pathol, FI-00029 Helsinki, Finland

[16] Tampere Univ Hosp, Palliat Unit, FI-33014 Tampere, Finland

[17] Tampere Univ Hosp, Sch Med, FI-33014 Tampere, Finland

[18] Univ Uppsala Hosp, Dept Oncol Radiol & Clin Immunol, SE-75185 Uppsala, Sweden

[19] Palacky Univ, Lab Genome Integr, CZ-77515 Olomouc, Czech Republic

来源：

NATURE GENETICS | 2008年 / 40卷 / 07期

基金：

芬兰科学院;

关键词：

D O I：

10.1038/ng.155

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1*2, rs1800566(T), NM_000903.2:c.558C>T) that disables NQO1 strongly predicts poor survival among two independent series of women with breast cancer (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53-aberrant tumors (P = 6.15 x 10(-5)). Survival after metastasis was reduced among NQO1*2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1*2-homozygous breast carcinoma cells in vitro, reflecting both p53-linked and p53-independent roles of NQO1. We propose a model of defective anthracycline response in NQO1-deficient breast tumors, along with increased genomic instability promoted by elevated reactive oxygen species (ROS), and suggest that the NQO1 genotype is a prognostic and predictive marker for breast cancer.

引用

页码：844 / 853

页数：10

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