作者：Jacquelyn K. Beals, PhD
出處：WebMD醫學新聞
September 2, 2008 — 一項新研究確認6種基因位置與慢性淋巴白血病（CLL）的感受性增加有關，這是歐洲族群常見的淋巴癌症，CLL顯然有很強的基因基礎，目前這項研究線上發表於8月31日的自然基因學期刊上，這是第一項顯示多重低風險變異可能與CLL遺傳型態有關的研究。
作者英國薩里蘇頓癌症研究機構血液腫瘤部門Daniel Catovsky醫學博士，在給Medscape病理學與實驗醫學的一封電子郵件中描述CLL的遺傳型態；CLL在東方比較少見，例如中國、日本，這清楚地支持基因因素是很重要的看法。Catovsky表示，也有建議指出低度惡性腫瘤在這些國家也比較少見。
B細胞CLL約佔所有白血病的四分之一，但是在亞洲人身上，僅佔成人白血病的不到5%；除此之外，將近10%的CLL病患表示一等親同樣罹患這樣的疾病。
Medscape病理學與實驗室醫學也接到來自Neil E. Caporaso博士的電子郵件評論，他是馬里蘭班塞斯達國家衛生研究院國家癌症機構基因流行病學與基因學部門，基因流行病學分部，藥物基因學組的主任；他表示，亞洲人罹患CLL的比例相當低。
Caporaso博士表示，我們並不了解原因為何，但是當亞洲人移民到高盛行率地區（例如美國），不像乳癌或是大腸癌，他們得到CLL的風險並未增加，這暗示，相較於環境因素來說，基因是很重要的。
目前這項基因體關聯性研究基因配對來自505位罹患CML病患與1438位控制組的DNA樣本，進行單一核苷酸多型性（SNPs）的分析。其結果再於額外1,529位CLL病患與3,115位控制組病患中確認；當所有數據合併在一起時，這六個低風險變異顯著地與CLL有關，範圍從1.91 x 10-20（IRF4）到3.96 x 10-9（PRKD2）。
這項研究中，與CLL感受性關係最強烈的兩個SNPs位於或接近第六對染色體的IRF4（干擾素調控因子4）；IRF4是淋巴球生長與增殖的關鍵調控因子，且影響記憶B細胞轉變為漿細胞；CLL與多發性骨髓瘤已經被證實與IRF4的表現有關。
Caporaso博士指出，就特定機轉來說，B細胞增殖為最受強烈懷疑的機轉之一，然而，細胞凋亡機轉也同樣可能，且免疫系統的部份缺失同樣列於清單之中。
第二個最受懷疑的區域位於第11對染色體，包括GRAMD18基因（GRAM區段，蛋白1B），這個區域目前並未被證實於B細胞淋巴增殖疾病扮演任何角色。
排行第三的區域（位於第15對染色體上）並沒有最接近的基因被證實與CLL感受性有關（P=4.51 x 10-12）；有證據顯示排行第四的區域，第2對染色體上的SP140，可能影響對免疫缺失病毒第一型的反應，並因此可能影響對其他抗原刺激的反應。
排名第五的區域位於解碼第2對染色體上乙醯輔酶A類氧化酶（ACOXL）基因，因為淋巴球並未表現這個基因，作者表示這可能有基因與SNP，而不是基因本身之間連鎖失衡的問題。
最後，這項研究確認的第六個區域位於解碼蛋白酶D2（PRKD2）的基因，這個基因的低度表現發生在不同B細胞淋巴瘤上，包括Burkitts氏淋巴瘤，且大約一半罹患CLL的病患身上。
在進一步的分析中，作者發現，並沒有證據指出任何已確認之區域間的交互作用（P>.09），然而，更多的變異區段則會增加發生CLL的風險；這六個區域都變異會增加發生CLL風險高達八倍。
新海園長島猶太醫學中心血液腫瘤部門主任、紐約布朗士艾柏愛因斯坦醫學院醫學教授Kanti R. Rai提供額外的評論；Rai教授觀察到，從發現一個病因未明疾病基因病理學的觀點看來，如果部分，而不是所有這六個區段與該疾病有關，將會是很好的；研究者確實已經發表令人信服的證據，證明這六個區段，每一個區段以我門目前的了解，在功能上都是獨立的；研究者在未來將可以確認這些發現，並試著決定這些區段是否彼此相關。
Rai教授表示，這項報導也看到無SNPs顯示與性別有顯著的關連，即使CLL比較常見於男性，在過去幾十年來，盛行率數據很穩定地顯示，男性與女性的比例約為1.7比1，且女性活得比較長，但是這六個感受性基因區段與性別之間沒什麼關聯並未讓我感到驚訝。
他附帶表示，在這項研究中（以最新進的科技細心地進行，且樣本數目相當大），研究者已經展示出CLL病理生成中第一個感受性的證據。
Catovsky博士、Caporaso博士與Rai教授表示並沒有相關資金上的往來。
Study Reports 6 Low-Risk Variants Conferring Risk for Chronic Lymphocytic Leukemia
By Jacquelyn K. Beals, PhD
Medscape Medical News
September 2, 2008 — A new study has identified 6 genetic loci associated with increased susceptibility to chronic lymphocytic leukemia (CLL). The most common lymphoid cancer in populations of European origin, CLL appears to have a strong genetic basis. The present study, published online August 31 in Nature Genetics, is the first to demonstrate that "multiple low-risk variants" may account for CLL's pattern of inheritance.
Author Daniel Catovsky, DSc(Med), FRCP, Section of Haemato-oncology, Institute of Cancer Research, Sutton, Surrey, United Kingdom, described the inheritance patterns of CLL in an email to Medscape Pathology and Lab Medicine. "CLL is less common in the far East: China, Japan...[which] clearly supports the view that genetic factors are important. There is a suggestion that other low-grade malignancies are also less common in those countries," said Dr. Catovsky.
B-cell CLL constitutes one fourth of all leukemias but less than 5% of adult leukemias in Asian populations. In addition, almost 10% of CLL patients report a first-degree relative with the disease.
Medscape Pathology and Lab Medicine also received email commentary from Neil E. Caporaso, MD, chief of the Pharmacogenetics Section, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. "CLL has one of the most striking racial disparities. Rates of CLL are sharply lower in Asians," he said.
"We don't understand the reason for this, but when Asians migrate to high-incidence areas like the [United States], unlike breast or colon [cancer], they do not acquire the higher rates characteristic of the new country. This suggests that genes are important, rather than environmental factors," said Dr. Caporaso.
The current genomewide association study genotyped single nucleotide polymorphisms (SNPs) from 505 DNA samples of patients with CLL and 1438 control patients. The results were validated in an additional 1529 patients with CLL and 3115 control patients. When all data were combined, P values for the 6 loci significantly associated with CLL ranged from 1.91 × 10?20 (IRF4) to 3.96 × 10?9 (PRKD2).
The strongest association with CLL susceptibility identified by the study was 2 SNPs in or near IRF4 (interferon regulatory factor 4) on chromosome 6. IRF4 is "a key regulator of lymphocyte development and proliferation" and influences the transformation of memory B cells into plasma cells. Both CLL and multiple myeloma have been linked to IRF4 expression.
"As for specific mechanisms, B-cell proliferation is one mechanism that is strongly suspected," said Dr. Caporaso. "However, apoptosis mechanisms are equally likely, and some defect in the immune system is certainly high on the list."
The second strongest association was for a region on chromosome 11 containing the gene for GRAMD1B (GRAM domain, protein 1B). This region is not currently known to have any role in B-cell lymphoproliferative diseases.
No "nearest gene" is recognized within the third-ranked region (on chromosome 15) associated with CLL susceptibility (P = 4.54 × 10?12). There are indications that the fourth-ranked region, SP140 on chromosome 2, may influence the response to immunodeficiency virus type 1 and so may affect the response to other antigenic challenges.
The fifth-ranked region is located in a gene that codes for acyl-coenzyme A oxidase-like (ACOXL) on chromosome 2. Because lymphocytes do not express this gene, the authors suggest that there may be "linkage disequilibrium" between this gene and a SNP outside of the gene itself.
Finally, the sixth locus identified by the study is in the gene encoding protein kinase D2 (PRKD2). Low expression of this gene occurs in various B-cell tumors, including Burkitt's lymphoma and roughly half of all patients with CLL.
In further analysis, the authors found no "evidence of interactive effects between any of the loci identified" (P > .09). However, the presence of more variant alleles increases the risk of developing CLL. Variation at all 6 loci can increase the risk for CLL as much as 8-fold.
Additional commentary was received via email from Kanti R. Rai, MD, chief of the Division of Hematology-Oncology, Long Island Jewish Medical Center, New Hyde Park, and professor of medicine, Albert Einstein College of Medicine, Bronx, both in New York.
"From the perspective of discovering the underlying genetic pathology of a disease for which the causative factors are unknown, it would have been nice if some, if not all, of these 6 loci had been related," Dr. Rai observed. "The investigators, indeed, have presented convincing evidence that the 6 loci, each to our current understanding, function independently of the other(s). It will be up to the future investigators to...confirm these findings and...try to determine if there are any of these [loci] which can be related to each other."
The report also noted that none of the SNPs showed a significant relationship with sex, despite the fact that CLL occurs more frequently in men. Dr. Rai noted: "[D]uring the past several decades the incidence data have consistently showed a male:female ratio of 1.7 to 1, and females living longer. But not finding a [sex] linkage in these 6 susceptibility loci does not surprise me."
He added, "In this study (which was meticulously conducted and with some of the most advanced technologies, with a relatively large sample size), the investigators have demonstrated a first evidence of susceptibility loci in the development of CLL."
Dr. Catovsky, Dr. Caporaso, and Dr. Rai have disclosed no relevant financial relationships.
Nat Genet. Published online August 31, 2008.
[ 本帖最後由 goodcat1111 於 2008-9-12 15:00 編輯 ] |
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