Ovarian carcinoma subtypes are different diseases: implications for biomarker studies.
Ovarian carcinoma subtypes are different diseases: implications for biomarker studies.
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DOI：
10.1371/journal.pmed.0050232
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发表时间：
2008-12-02
期刊：
影响因子：
15.8
通讯作者：
Huntsman D
中科院分区：
文献类型：
--
作者：
Köbel M;Kalloger SE;Boyd N;McKinney S;Mehl E;Palmer C;Leung S;Bowen NJ;Ionescu DN;Rajput A;Prentice LM;Miller D;Santos J;Swenerton K;Gilks CB;Huntsman D
尽管人们早就认识到卵巢癌亚型（浆液性、透明细胞性、子宫内膜样和黏液性）与不同的自然病史相关，但大多数卵巢癌生物标志物研究和目前针对该疾病女性的治疗方案并不具有亚型特异性。随着高通量分子技术的出现，在这些亚型中已经确定了不同的发病途径。我们研究了不同亚型之间生物标志物表达率的变化，以及这如何影响生物标志物表达与诊断或预后阶段之间的相关性。在这项回顾性研究中，我们评估了21种候选组织生物标志物（CA125、CRABP-II、EpCam、ER、F-Spondin、HE4、IGF2、K-Cadherin、Ki-67、KISS1、Matriptase、Mesothelin、MIF、MMP7、p21、p53、PAX8、PR、SLPI、TROP2、WT1）在1984年至2000年期间收集的500例卵巢癌人群队列中的蛋白表达。21种生物标志物中有20种的表达在亚型之间存在显著差异，但在每个亚型内的不同阶段没有差异。生存分析显示，21个生物标志物中有9个是整个队列的预后指标，但按亚型分析时，在高级别浆液型中只有3个仍然是预后指标，在透明细胞亚型中没有。例如，通过Ki-67染色评估的肿瘤增殖在不同亚型之间差异显著，并且在整个队列中是一个不利的预后标志物（风险比[RR] 1.7, 95%置信区间[CI] 1.2%-2.4%），但在任何亚型中都没有预后意义。与特定亚型相比，预后关联甚至可以在整个队列中显示出负相关。例如，WT1更常在高级别浆液性癌中表达，这是一种侵袭性亚型，在整个卵巢癌队列中是一个不利的预后标志物（RR为1.7,95% CI为1.2%-2.3%），但在高级别浆液性亚型中是一个有利的预后标志物（RR为0.5,95% CI为0.3%-0.8%）。生物标志物表达与生存率的相关性在不同亚型之间存在很大差异，在全队列分析中很容易被忽视。为了避免这种影响，应该对队列中的每个亚型进行离散分析。卵巢癌亚型是不同的疾病，这些差异应体现在临床研究研究设计中，最终体现在卵巢癌的治疗中。David Huntsman及其同事描述了不同卵巢癌亚型中生物标志物表达模式与生存之间的关系。他们认为卵巢癌的治疗应该反映这些亚型之间的差异。每年，大约有20万女性患上卵巢癌，10万多人死于这种疾病。卵巢上皮性癌（癌）发生时，卵巢或输卵管上皮细胞发生突变或类似的变化，使它们在卵巢（骨盆中产生卵子的两个小器官）中不受控制地生长，并具有在全身扩散（转移）的潜力。虽然癌症局限于卵巢，但癌症专家称其为第一阶段疾病；70%-80%被诊断为第一阶段卵巢癌的女性至少能存活5年。然而，只有五分之一的卵巢癌在这一阶段被诊断出来；在大多数患者中，癌症已经扩散到骨盆（II期疾病），进入腹腔（肠、胃和肝脏周围的空间；III期疾病），或转移到远处器官，如大脑（IV期疾病）。这种腹膜扩散可能只伴有模糊的腹痛和轻微的消化障碍。晚期卵巢癌患者采用手术和化疗相结合的治疗方法，但是，尽管最近治疗取得了进展，只有15%被诊断为IV期疾病的妇女能存活5年。尽管IV期通常被视为一种疾病，但实际上卵巢癌有几种不同的亚型。根据其显微外观分为高级别浆液性、低级别浆液性、透明细胞性、子宫内膜样癌和粘液性卵巢癌。这些亚型发展不同，对化疗的反应也不同。然而，研究卵巢癌的科学家通常将这种癌症视为单一的实体，目前针对这种疾病的治疗方案并不是针对特定亚型的。如果将每一种亚型作为一种单独的疾病来治疗，是否会在了解卵巢癌和改善治疗方面取得更好的进展？为什么有些肿瘤局限于卵巢，而大多数肿瘤在诊断时已扩散到卵巢以外？在这项研究中，研究人员通过询问“生物标志物”（由癌细胞产生的可用于检测肿瘤和监测治疗效果的分子）的表达与诊断阶段或生存时间之间的相关性是否可以通过卵巢癌不同亚型之间的差异生物标志物表达来解释，从而解决了这些问题。他们还解决了早期卵巢癌和晚期卵巢癌是否存在根本不同的问题。1984年至2000年间，研究人员在加拿大不列颠哥伦比亚省收集的500份卵巢癌样本中测量了21种候选蛋白质生物标志物的表达。对于其中的20种生物标志物，表达该生物标志物的肿瘤比例在卵巢癌亚型之间存在显著差异。综合考虑所有肿瘤，10种生物标志物在早期和晚期肿瘤中表达水平不同。然而，当每个亚型单独考虑时，没有一种生物标志物的表达随分期而变化。当研究人员询问是否有任何生物标志物的表达与生存时间相关时，他们发现，当所有肿瘤一起考虑时，九种生物标志物是结果的不利指标。也就是说，肿瘤表达这些生物标志物的女性比肿瘤不表达这些生物标志物的女性死于卵巢癌的风险更高。然而，只有三个生物标志物是单独考虑的高级别浆液性癌的不利指标，并且WT1生物标志物在该亚型卵巢癌中的表达与较低的死亡风险相关。同样，当考虑所有肿瘤时，生物标志物Ki-67的表达是一个不利的预后指标，但不是任何个体亚型的预后指标。这些和其他研究结果表明，生物标志物的表达与卵巢癌亚型的关系比与分期的关系更强。换句话说，从早期到晚期，生物标志物的表达是恒定的，但仅在给定的亚型中。其次，不同亚型的生物标志物表达与生存的关系不同，因此将所有亚型混为一谈可能会产生误导性的结果。尽管这些发现需要在更多的肿瘤样本中得到证实，但它们支持了卵巢癌亚型是不同疾病的观点。因此，在实践中，这些发现表明，如果未来的生物标志物研究和临床研究分别调查卵巢癌的每种亚型，而不是将它们归类在一起，就更有可能找到更好的检测和治疗卵巢癌的方法。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0050232访问这些网站。美国国家癌症研究所为患者和专业人员提供了一个简短的描述，介绍了癌症是什么，它是如何发展的，以及卵巢癌各方面的信息。英国慈善机构Cancerbackup提供了关于癌症的一般信息和更具体的卵巢癌信息，包括肿瘤分期
Although it has long been appreciated that ovarian carcinoma subtypes (serous, clear cell, endometrioid, and mucinous) are associated with different natural histories, most ovarian carcinoma biomarker studies and current treatment protocols for women with this disease are not subtype specific. With the emergence of high-throughput molecular techniques, distinct pathogenetic pathways have been identified in these subtypes. We examined variation in biomarker expression rates between subtypes, and how this influences correlations between biomarker expression and stage at diagnosis or prognosis. In this retrospective study we assessed the protein expression of 21 candidate tissue-based biomarkers (CA125, CRABP-II, EpCam, ER, F-Spondin, HE4, IGF2, K-Cadherin, Ki-67, KISS1, Matriptase, Mesothelin, MIF, MMP7, p21, p53, PAX8, PR, SLPI, TROP2, WT1) in a population-based cohort of 500 ovarian carcinomas that was collected over the period from 1984 to 2000. The expression of 20 of the 21 biomarkers differs significantly between subtypes, but does not vary across stage within each subtype. Survival analyses show that nine of the 21 biomarkers are prognostic indicators in the entire cohort but when analyzed by subtype only three remain prognostic indicators in the high-grade serous and none in the clear cell subtype. For example, tumor proliferation, as assessed by Ki-67 staining, varies markedly between different subtypes and is an unfavourable prognostic marker in the entire cohort (risk ratio [RR] 1.7, 95% confidence interval [CI] 1.2%–2.4%) but is not of prognostic significance within any subtype. Prognostic associations can even show an inverse correlation within the entire cohort, when compared to a specific subtype. For example, WT1 is more frequently expressed in high-grade serous carcinomas, an aggressive subtype, and is an unfavourable prognostic marker within the entire cohort of ovarian carcinomas (RR 1.7, 95% CI 1.2%–2.3%), but is a favourable prognostic marker within the high-grade serous subtype (RR 0.5, 95% CI 0.3%–0.8%). The association of biomarker expression with survival varies substantially between subtypes, and can easily be overlooked in whole cohort analyses. To avoid this effect, each subtype within a cohort should be analyzed discretely. Ovarian carcinoma subtypes are different diseases, and these differences should be reflected in clinical research study design and ultimately in the management of ovarian carcinoma. David Huntsman and colleagues describe the associations between biomarker expression patterns and survival in different ovarian cancer subtypes. They suggest that the management of ovarian cancer should reflect differences between these subtypes. Every year, about 200,000 women develop ovarian cancer and more than 100,000 die from the disease. Ovarian epithelial cancer (carcinoma) occurs when epithelial cells from the ovary or fallopian tube acquire mutations or equivalent changes that allow them to grow uncontrollably within one of the ovaries (two small organs in the pelvis that produce eggs) and acquire the potential to spread around the body (metastasize). While the cancer is confined to the ovaries, cancer specialists call this stage I disease; 70%–80% of women diagnosed with stage I ovarian cancer survive for at least 5 y. However, only a fifth of ovarian cancers are diagnosed at this stage; in the majority of patients the cancer has spread into the pelvis (stage II disease), into the peritoneal cavity (the space around the gut, stomach, and liver; stage III disease), or metastasized to distant organs such as brain (stage IV disease). This peritoneal spread might be associated with often only vague abdominal pain and mild digestive disturbances. Patients with advanced-stage ovarian carcinoma are treated with a combination of surgery and chemotherapy but, despite recent advances in treatment, only 15% of women diagnosed with stage IV disease survive for 5 y. Although it is usually regarded as a single disease, there are actually several distinct subtypes of ovarian carcinoma. These are classified according to their microscopic appearance as high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous ovarian carcinomas. These subtypes develop differently and respond differently to chemotherapy. Yet scientists studying ovarian carcinoma usually regard this cancer as a single entity, and current treatment protocols for the disease are not subtype specific. Might better progress be made toward understanding ovarian carcinoma and toward improving its treatment if each subtype were treated as a separate disease? Why are some tumors confined to the ovary, whereas the majority spread beyond the ovary at time of diagnosis? In this study, the researchers address these questions by asking whether correlations between the expression of “biomarkers” (molecules made by cancer cells that can be used to detect tumors and to monitor treatment effectiveness) and the stage at diagnosis or length of survival can be explained by differential biomarker expression between different subtypes of ovarian carcinoma. They also address the question of whether early stage and late stage ovarian carcinomas are fundamentally different. The researchers measured the expression of 21 candidate protein biomarkers in 500 ovarian carcinoma samples collected in British Columbia, Canada, between 1984 and 2000. For 20 of the biomarkers, the fraction of tumors expressing the biomarker varied significantly between ovarian carcinoma subtypes. Considering all the tumors together, ten biomarkers had different expression levels in early and late stage tumors. However, when each subtype was considered separately, the expression of none of the biomarkers varied with stage. When the researchers asked whether the expression of any of the biomarkers correlated with survival times, they found that nine biomarkers were unfavorable indicators of outcome when all the tumors were considered together. That is, women whose tumors expressed any of these biomarkers had a higher risk of dying from ovarian cancer than women whose tumors did not express these biomarkers. However, only three biomarkers were unfavorable indicators for high-grade serous carcinomas considered alone and the expression of a biomarker called WT1 in this subtype of ovarian carcinoma is associated with a lower risk of dying. Similarly, expression of the biomarker Ki-67 was an unfavorable prognostic indicator when all the tumors were considered, but was not a prognostic indicator for any individual subtype. These and other findings indicate that biomarker expression is more strongly associated with ovarian carcinoma subtype than with stage. In other words, biomarker expression is constant from early to late stage, but only within a given subtype. Second, the association of biomarker expression with survival varies between subtypes, hence lumping all subtypes together can yield misleading results. Although these findings need confirming in more tumor samples, they support the view that ovarian carcinoma subtypes are different diseases. In practical terms, therefore, these findings suggest that better ways to detect and treat ovarian cancer are more likely to be found if future biomarker studies and clinical research studies investigate each subtype of ovarian carcinoma separately rather than grouping them all together. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050232. The US National Cancer Institute provides a brief description of what cancer is and how it develops and information on all aspects of ovarian cancer for patients and professionals. It also provides a fact sheet on tumor markers (in English and Spanish) The UK charity Cancerbackup provides general information about cancer and more specific information about ovarian cancer, including tumor staging
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影响因子：
45.3
作者：
Anttila, M;Kosma, VM;Syrjanen, K
通讯作者：
Syrjanen, K
影响因子：
10.3
作者：
du Bois, A;Lück, HJ;Pfisterer, J
通讯作者：
Pfisterer, J
影响因子：
9.3
作者：
Prentice LM;Klausen C;Kalloger S;Köbel M;McKinney S;Santos JL;Kenney C;Mehl E;Gilks CB;Leung P;Swenerton K;Huntsman DG;Aparicio SA
通讯作者：
Aparicio SA
影响因子：
3.7
作者：
Palmer C;Duan X;Hawley S;Scholler N;Thorpe JD;Sahota RA;Wong MQ;Wray A;Bergan LA;Drescher CW;McIntosh MW;Brown PO;Nelson BH;Urban N
通讯作者：
Urban N
影响因子：
45.3
作者：
Menon, U;Skates, SJ;Jacobs, IJ
通讯作者：
Jacobs, IJ