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【资讯翻译】Gene Mutation Signals Poor Prognosis for Pancreatic Tumors

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发表于 2015-10-12 15:15:16 | 显示全部楼层 |阅读模式

Gene Mutation Signals Poor Prognosis for Pancreatic Tumors

NASHVILLE, Tennessee — For patients with pancreatic neuroendocrine tumors, the presence of recently identified mutations in two key genes is a prognostic factor for poor outcome, researchers report.

"We found loss of nuclear expression in about 23% of the tumors that we studied, and this loss of expression was associated with worse tumors from the outset," lead investigator Michelle Heayn, MD, a second-year pathology resident at the University of Pittsburgh Medical Center, told Medscape Medical News.

Pancreatic tumors with neuroendocrine histology frequently respond to chemotherapy and have a more favorable prognosis than the more common pancreatic adenocarcinomas. However, the mutations are associated with worse disease-free and disease-specific survival.

The results of the study were presented here at the College of American Pathologists 2015 Meeting.

The mutations — in the alpha-thalassemia mental retardation syndrome X-linked gene (ATRX) and the death-domain-associated protein gene (DAXX) — cause loss of expression of the proteins coded by ATRX and DAXX, Dr Heayn explained.

To test whether these mutations had any prognostic significance, Dr Heayn and her colleagues used immunolabeling in surgically resected pancreatic neuroendocrine tumors from 303 patients. They then correlated the findings with patient demographics, pathologic features, disease-free survival, and disease-specific survival. Follow-up ranged from 1.6 to 18.8 years.

Of the 303 tumors, 69 (23%) had mutations in one or both genes. Tumors with a gene mutation had a larger mean diameter than tumors with intact gene expression (5.0 vs 2.4 cm), as well as a significantly higher histologic grade, more lymphovascular and perineural invasion, a more advanced T stage, greater lymph node involvement, more synchronous metastases, and more frequent disease recurrence (P < .01 for all comparisons).

In addition, the mutations were associated with shorter mean disease-free survival (5.6 vs 17.2 years; P < .01) and shorter mean disease-specific survival (12.5 vs 17.7 years; P = .01).

On multivariate analysis that controlled for patient and tumor factors, the mutations were a significant predictor of shorter disease-free survival (P < .01), independent of tumor size, stage, histology, lymphovascular or perineural invasion, and lymph node status.

Dr Heayn and her colleagues are currently exploring whether there is an association between metastatic pancreatic cancer and these genetic mutations.

Metastatic Pancreatic Cancer

Patients with these mutations in their tumors should be followed more closely for recurrence or disease progression, Dr Heayn said. And in this subset of patients, there is the possibility of new targeted therapies.

These findings are very important, said Safia Salaria, MD, from the Vanderbilt University Medical Center in Nashville.

"There is so much heterogeneity in these tumors, and currently we are just using clinicopathologic features and the WHO-recommended Ki-67 labelling and white count," she told Medscape Medical News.

"If we have something that can be an adjunct to that — immunohistochemistry to determine the loss of these genes — it's definitely going to be something that will help us, especially in low-grade tumors," she explained.

Staining for the expression of the genes could also help pathologists identify patients who are at higher risk for disease recurrence or metastasis but don't have metastases at the time of primary resection, Dr Salaria said.

信源地址:http://www.medscape.com/viewarticle/852457

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发表于 2015-10-12 15:37:36 | 显示全部楼层
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发表于 2015-10-13 14:32:04 | 显示全部楼层
基因突变对胰腺肿瘤预后的不良影响
美国田纳西州——研究人员报告称,对于胰腺神经内分泌肿瘤的患者来说,最近发现的两个关键基因突变是一种不良预后的影响因素。
“在我们研究的肿瘤中,约有23%发现了核表达缺失,这种表达缺失与一开始就更糟糕的肿瘤有关,”首席研究员Michelle Heayn博士告诉Medscape医学新闻,她是匹兹堡大学医学中心在职第二年的病理学住院医师。
神经内分泌胰腺肿瘤的组织学经常对化疗有反应,比更常见的胰腺癌有更有利的预后。然而,突变与较差的无病和疾病特异性生存期相关。
本研究的结果在2015美国病理学会会议上发表。
Dr Heayn博士解释说,这两个突变分别发生在α地中海贫血智力低下综合征X连锁基因(ATRX)和死亡结构域相关蛋白基因(DAXX)上,造成ATRXDAXX编码的蛋白表达缺失。
为了测试这些突变是否有预后意义,Heayn博士和她的同事们对303例患者手术切除的胰腺神经内分泌肿瘤使用了免疫标记。然后他们将试验结果与患者的人口统计资料、病理学特征、无病生存期和疾病特异性生存期相关联。随访期为1.6-18.8年。
在这303例肿瘤中,69例(23%)有一个或两个基因突变。有基因突变的肿瘤比完整基因表达的肿瘤的平均直径大(5.0 vs 2.4 cm),并且组织学分级更高、淋巴管和神经浸润更多、T阶段更晚期、淋巴结转移更严重、同步转移更多、疾病复发频繁更高(所有的比较P0.01)。
此外,突变与更短的平均无病生存期(5.6 vs 17.2年;P<0.01)和更短的平均疾病特异性生存期(12.5 vs 17.7年;P=0.01)相关。
在以患者和肿瘤因素为对照的多变量分析中,突变是较短的无病生存期的显著预测因素(P<0.01),独立于肿瘤体积、阶段、组织、淋巴管或神经浸润、淋巴结状态。
Heayn博士和她的同事们目前正在研究,转移性胰腺癌与这些遗传突变之间是否有关联。
转移性胰腺癌

Dr Heayn博士认为,那些肿瘤中有突变的患者需要密切随访复发或病情进展。在这部分患者中,有新的靶向治疗的可能性。

Safia Salaria博士(医学博士,来自范德比尔特大学医学中心)认为这些发现非常重要。

“这些肿瘤中的异质性非常多,目前我们只利用了临床病理学特征和WHO推荐的Ki-67标记以及白细胞计数。”她告诉Medscape医学新闻说。

“如果我们有些什么可以辅助免疫组化检测这些缺失基因的东西,那将对我们会有显著的帮助,特别是在低级别肿瘤中。”她解释说。
Salaria博士说,基因表达染色能帮助医生鉴定那些在原发性肿瘤切除后复发风险高或尚无转移灶但转移风险高的患者。。

英文原文:
Gene Mutation Signals Poor Prognosis for Pancreatic Tumors

NASHVILLE, Tennessee — For patients with pancreatic neuroendocrine tumors, thepresence of recently identified mutations in two key genes is a prognosticfactor for poor outcome, researchers report.

"We found loss of nuclear expression in about 23% of the tumors that westudied, and this loss of expression was associated with worse tumors from theoutset," lead investigator Michelle Heayn, MD, a second-year pathologyresident at the University of Pittsburgh Medical Center, told Medscape MedicalNews.

Pancreatic tumors with neuroendocrine histology frequently respond tochemotherapy and have a more favorable prognosis than the more commonpancreatic adenocarcinomas. However, the mutations are associated with worsedisease-free and disease-specific survival.

The results of the study were presented here at the College of AmericanPathologists 2015 Meeting.

The mutations — in the alpha-thalassemia mental retardation syndrome X-linkedgene (ATRX) and the death-domain-associated protein gene (DAXX) — cause loss ofexpression of the proteins coded by ATRX and DAXX, Dr Heayn explained.

To test whether these mutations had any prognostic significance, Dr Heayn andher colleagues used immunolabeling in surgically resected pancreaticneuroendocrine tumors from 303 patients. They then correlated the findings withpatient demographics, pathologic features, disease-free survival, anddisease-specific survival. Follow-up ranged from 1.6 to 18.8 years.

Of the 303 tumors, 69 (23%) had mutations in one or both genes. Tumors with agene mutation had a larger mean diameter than tumors with intact geneexpression (5.0 vs 2.4 cm), as well as a significantly higher histologic grade,more lymphovascular and perineural invasion, a more advanced T stage, greaterlymph node involvement, more synchronous metastases, and more frequent diseaserecurrence (P < .01 for all comparisons).

In addition, the mutations were associated with shorter mean disease-freesurvival (5.6 vs 17.2 years; P < .01) and shorter mean disease-specificsurvival (12.5 vs 17.7 years; P = .01).

On multivariate analysis that controlled for patient and tumor factors, themutations were a significant predictor of shorter disease-free survival (P <.01), independent of tumor size, stage, histology, lymphovascular or perineuralinvasion, and lymph node status.

Dr Heayn and her colleagues are currently exploring whether there is anassociation between metastatic pancreatic cancer and these genetic mutations.

Metastatic Pancreatic Cancer

Patients with these mutations in their tumors should be followed more closelyfor recurrence or disease progression, Dr Heayn said. And in this subset ofpatients, there is the possibility of new targeted therapies.

These findings are very important, said Safia Salaria, MD, from the VanderbiltUniversity Medical Center in Nashville.

"There is so much heterogeneity in these tumors, and currently we are justusing clinicopathologic features and the WHO-recommended Ki-67 labelling andwhite count," she told Medscape Medical News.

"If we have something that can be an adjunct to that —immunohistochemistry to determine the loss of these genes — it's definitelygoing to be something that will help us, especially in low-grade tumors,"she explained.

Staining for the expression of the genes could also help pathologists identifypatients who are at higher risk for disease recurrence or metastasis but don'thave metastases at the time of primary resection, Dr Salaria said.

信源地址:http://www.medscape.com/viewarticle/852457

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发表于 2015-10-13 15:30:05 | 显示全部楼层
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