俄勒岡健康與科學(xué)大學(xué)（OHSU）Knight癌癥研究所的研究發(fā)現(xiàn),，一群有缺陷的蛋白質(zhì),，被懷疑導(dǎo)致了機(jī)體修復(fù)自身DNA能力的故障，科學(xué)家們可能正好需要這群蛋白來證明一類新藥在治療廣泛的卵巢癌患者中的有效性,。
這些研究結(jié)果發(fā)表在這周的PLoS ONE上,，已引發(fā)更多關(guān)于靶向聚腺苷二磷酸核糖聚合酶（PARP）藥物臨床試驗(yàn)中病人人數(shù)是否應(yīng)該擴(kuò)大的探討,。一些類型癌癥的生長比正常細(xì)胞更依賴于PARP，這就意味著當(dāng)這些酶發(fā)生混亂時(shí)靶向它們是一種治療卵巢癌的潛在有效方法,。目前,，PARP抑制劑正在有兩類機(jī)能障礙蛋白（即BRCA 1和BRCA 2）的患者身上進(jìn)行測試。但是,，OHSU Knight癌癥研究所對除BRCA蛋白以外的其他蛋白進(jìn)行了研究,，結(jié)果表明它們也發(fā)揮了驅(qū)動(dòng)卵巢癌的作用。
接近PARP抑制劑的潛力可以改變卵巢癌治療的動(dòng)力學(xué),。在過去的二十年里,，卵巢癌的治療選擇還沒有大幅度增加，OHSU Knight癌癥研究所的婦科腫瘤學(xué)家Tanja Pejovic博士這樣說,。Pejovic主持這些額外缺陷蛋白的研究,，她補(bǔ)充到，結(jié)果提供進(jìn)一步研究多種蛋白的作用證據(jù),，這是必要的,。
只有大約10%至15%的患卵巢癌婦女存在有BRCA1或BRCA2突變。Pejovic對186例非遺傳性癌癥患者進(jìn)行研究,，發(fā)現(xiàn)41%疾病早期復(fù)發(fā)的患者也有追蹤的其他蛋白質(zhì)水平的異常,。相比之下，只有19.5%的患者在三年內(nèi)有這些蛋白質(zhì)水平的異常,，這些患者還沒有發(fā)生過疾病復(fù)發(fā),。
"如果我們能夠鑒定出區(qū)分這些患者早期復(fù)發(fā)風(fēng)險(xiǎn)的蛋白質(zhì)，這將在卵巢癌的治療上打開一個(gè)新方向",，Pejovic說,。
這項(xiàng)研究--由Sherie Hildreth卵巢癌（SHOC）基金會資助--集中在可以在修復(fù)有害DNA鏈斷裂中幫助細(xì)胞的蛋白質(zhì)，這一過程稱為同源重組（HR）,。卵巢癌中的同源重組機(jī)能障礙還沒有被很好理解,，在那里沒有這種疾病的家族史。然而,，有證據(jù)表明,，這些蛋白質(zhì)的影響病人對藥物的反應(yīng)能力和他們治療后的生存率。
卵巢癌是第二常見的婦科癌癥,，也是患婦科癌癥婦女的最常見死亡原因,。每年大約21000例卵巢癌病例被診斷，每年約14000人死于此疾病,。
OHSU Knight癌癥研究所,，有助于個(gè)性化癌癥醫(yī)學(xué)的先鋒領(lǐng)域，致力于鑒定驅(qū)動(dòng)每個(gè)患者癌癥的特異變異的研究,。對該研究做了貢獻(xiàn)的OHSU Knight癌癥研究所的其他研究人員是：Weiya Z. Wysham醫(yī)學(xué)博士,，Hong Li碩士/醫(yī)學(xué)博士,，Laura Hays博士，Jay Wright博士,， Nupur Pande博士和Maureen Hoatlin博士,。（生物谷bioon.com）
doi:10.1371/journal.pone.0030042
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BRCAness Profile of Sporadic Ovarian Cancer Predicts Disease Recurrence
Weiya Z. Wysham, Paulette Mhawech-Fauceglia, Hong Li, Laura Hays, Suzanna Syriac, Tijana Skrepnik, Jay Wright, Nupur Pande, Maureen Hoatlin, Tanja Pejovic
Abstract Background The consequences of defective homologous recombination (HR) are not understood in sporadic ovarian cancer, nor have the potential role of HR proteins other than BRCA1 and BRCA2 been clearly defined. However, it is clear that defects in HR and other DNA repair pathways are important to the effectiveness of current therapies. We hypothesize that a subset of sporadic ovarian carcinomas may harbor anomalies in HR pathways, and that a BRCAness profile (defects in HR or other DNA repair pathways) could influence response rate and survival after treatment with platinum drugs. Clinical availability of a BRCAness profile in patients and/or tumors should improve treatment outcomes. Objective To define the BRCAness profile of sporadic ovarian carcinoma and determine whether BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression correlates with response to treatment, disease recurrence, and recurrence-free survival. Materials and Methods Protein microarray analysis of ovarian cancer tissue was used to determine protein expression levels for defined DNA repair proteins. Correlation with clinical and pathologic parameters in 186 patients with advanced stage III-IV and grade 3 ovarian cancer was analyzed using Chi square, Kaplan-Meier method, Cox proportional hazard model, and cumulative incidence function. Results High PARP, FANCD2 and BRCA1 expressions were significantly correlated with each other; however, elevated p53 expression was associated only with high PARP and FANCD2. Of all patients, 9% recurred within the first year. Among early recurring patients, 41% had high levels of PARP, FANCD2 and P53, compared to 19.5% of patients without early recurrence (p = 0.04). Women with high levels of PARP, FANCD2 and/or P53 had first year cumulative cancer incidence of 17% compared with 7% for the other groups (P = 0.03). Conclusions Patients with concomitantly high levels of PARP, FANCD2 and P53 protein expression are at increased risk of early ovarian cancer recurrence and platinum resistance.
