基因簽名與乳癌存活有關


  January 17, 2007 — 研究者鑑定了一種與中型分化乳癌病患臨床結果有關的基因表現簽名— 這一類病患的預後通常是難以評估的;在登載於1月18日新英格蘭醫學期刊的報告中,研究者指出腫瘤發生細胞之基因簽名不同的病患其10年復發率差異相當大,他們依照所謂的侵襲性基因簽名將這些病患分類, 可以預判之中的病患超過90%會發生轉移病症。
  
  本研究是密西根大學的Rui Liu博士所領導,研究者報告指出,乳癌病患的基因簽名和傷應簽名(wound-response signature)合併考量可以更強烈的與臨床結果有關。
  
  紐約史隆凱特琳紀念癌症中心Howard Hughes醫學研究中心之癌症生物與基因計畫的Joan Massague博士在編輯評論中表示,這些發現是令人感到刺激的,他指出,由Liu和同事所發表的基因表現可能不只和乳癌病患的存活率有關,也和肺癌、前列腺癌以及神經管母細胞瘤有關。
  
  但是,Massague醫師也提出有關此一發現和其臨床關聯的關懷,他表示,這些是相當令人興奮的結果,但令人挫敗的現實是基因組在各種研究中是相當不同的,令人質疑他們的生物特性和臨床衝擊;他指出,雖然腫瘤發生的乳癌細胞造成侵襲性基因簽名的預測力,這簽名可能有數種因素組成,包括腫瘤發生和非腫瘤發生的乳癌細胞。
  
  Massague醫師指出,腫瘤發生或非腫瘤發生的乳癌細胞與正常乳房上皮細胞的比較,在本研究中發現有將近60%的基因是相同的;由侵襲性基因簽名預測的不良結果之平均風險比約為 30%,超過非腫瘤發生的乳癌細胞與正常乳房上皮細胞的基因簽名所預測的。
  
  【腫瘤生長受癌症幹細胞驅動?】
  根據編輯評論,本研究的想法之一為腫瘤生長的可能性是受多潛能幹細胞驅動,認為癌症幹細胞是來自血液方面癌症,這方面的幹細胞研究已經有一定成果;Massague醫師指出,在腫瘤出現這一類的幹細胞是十分有趣的,特別是這些腫瘤存在少數結果卻是最阻抗治療的。
  
  根據Liu醫師和同事所述,乳癌包含一少部分的癌細胞,特徵是CD44表現和CD24低或無法測得CD24,比其他類的癌症細胞有更高的腫瘤發生能力 ;為了此一研究,研究者比較低腫瘤發生乳癌細胞和正常乳房上皮細胞的CD44+CD24-的基因表現;不同表現的基因產生186種侵襲性基因簽名,用以評估乳癌或其他癌症病患的整體存活率和無轉移存活率的關聯。
  
  研究者發現,侵襲性基因簽名和整體存活率以及無轉移乳癌存活率之間有顯著的關聯(兩者之P均 < .001),這個關聯與已知的臨床和病理變項無關;若合併國家健康中心的預後規範,基因簽名被用來將高風險初期乳癌病患預後分類分成好或不好。
  
  預後好的病患中,10年無轉移存活率是81%,預後不好的病患則是57%;和該簽名有關的還有神經管母細胞瘤medulloblastoma (P = .004)、肺癌 (P = .03) 以及前列腺癌(P = .01)等之預後。
  
  Massague醫師在他的編輯評論中指出,這些發現引起了一些新的問題,首先,少數幹細胞模式的基因表現如何能足以偵測大型的腫瘤?一個解釋是侵犯的腫瘤可能富含癌症幹細胞;他補充說明,這種觀點和腫瘤發生乳癌細胞是少數的描述不同。
  
  Massague醫師表示,一個不同的解釋是認為,侵襲性基因簽名是從腫瘤發生的乳癌細胞和正常的乳房上皮細胞比較而得,而不是非腫瘤發生的乳癌細胞,這可能代表致癌轉型細胞的簽名;藉由比較,基因表現的改變對觀察發現之腫瘤發生的乳癌細胞和非腫瘤發生的乳癌細胞之間之差異是不廣泛的。
  
  N Engl J Med 2007;356:217-226, 294.

Gene Signature Linked to Breas

By Allison Gandey
Medscape Medical News

January 17, 2007 ??Researchers have identified a gene-expression signature that may be linked to clinical outcome in breast cancer patients with intermediate-grade differentiation ??a group whose prognosis is typically difficult to assess. Reporting in the January 18 issue of the New England Journal of Medicine, investigators say that patients with different genetic signatures of tumorigenic cells had very different 10-year relapse rates and that by classifying these patients with what they are calling the invasiveness gene signature, they could predict which of the more than 90% of patients would develop metastatic disease.

"This genetic signature was even more strongly associated with clinical outcomes when combined with the wound-response signature in breast cancer," report the researchers, led by Rui Liu, PhD, from the University of Michigan at Ann Arbor.

In an accompanying editorial, Joan Massague, PhD, from the Cancer Biology and Genetics Program and the Howard Hughes Medical Institute, at the Memorial Sloan-Kettering Cancer Center, in New York, called the findings provocative. He notes that the gene expression reported by Liu and colleagues may be associated with survival not only in breast cancer, but also in lung cancer, prostate cancer, and medulloblastoma.

But Dr. Massague; also raises concerns about the finding and its clinical relevance in particular. "These are exciting results," he writes, "but the disconcerting reality is that the gene sets in the various studies are largely nonoverlapping, raising questions about their biologic significance and clinical implications." He notes that although tumorigenic breast cancer cells contributed to the predictive power of the invasiveness gene signature, the signature may comprise several factors that are shared by tumorigenic and nontumorigenic breast cancer cells.

Dr. Massagute; points out that a comparison of tumorigenic or nontumorigenic breast cancer cells with normal breast epithelial cells resulted in an overlap in the lists of genes of approximately 60% in the study. The average hazard ratio for a poor outcome as predicted by the invasiveness gene signature was about 30% greater than that predicted by signatures derived from comparisons between nontumorigenic breast cancer cells and normal breast epithelial cells.

Tumor Growth Driven by Cancer Stem Cells?

According to the editorialist, the idea for studies such as this one exploring the possibility that tumor growth is driven by pluripotent cells considered cancer stem cells comes from work in the hematologic cancers, where stem-cell research is well established. "The presence of such stem cells in a tumor is of great interest, especially if these tumor-perpetuating minorities turn out to be the cell populations most resistant to therapy," Dr. Massagute; notes.

According to Dr. Liu and colleagues, breast cancers contain a minority population of cancer cells characterized by CD44 expression and low or undetectable levels of CD24 that have higher tumorigenic capacity than other subtypes of cancer cells. For their study, the researchers compared the gene-expression profile of CD44+CD24??/i>/low tumorigenic breast cancer cells with that of normal breast epithelium. Differentially expressed genes were used to generate a 186-gene invasiveness signature, which was evaluated for its association with overall survival and metastasis-free survival in patients with breast cancer or other types of cancer.

The investigators found there was a significant association between the invasiveness gene signature and both overall and metastasis-free breast cancer survival (P < .001 for both). This link was independent of established clinical and pathological variables. When combined with the prognostic criteria of the National Institutes of Health, the gene signature was used to stratify patients with high-risk early breast cancer into prognostic categories ??good or poor.

Among patients with a good prognosis, the 10-year rate of metastasis-free survival was 81%, and among those with a poor prognosis, it was 57%. The signature was also associated with the prognosis in medulloblastoma (P = .004), lung cancer (P = .03), and prostate cancer (P = .01).

These findings raise a number of new questions, Dr. Massagute; points out in his editorial. "First, how can the gene-expression pattern of a minority stem-cell?like population be dominant enough to be detectable in bulk tumors?" One interpretation is that aggressive tumors may be rich in cancer stem cells. This view, he adds, is at odds with the description of tumorigenic breast cancer cells as a minority population.

"An alternative explanation is suggested by the fact that the invasiveness gene signature was obtained by comparing tumorigenic breast cancer cells with normal breast epithelial cells, and not with nontumorigenic breast cancer cells. This may represent a signature of oncogenically transformed cells," Dr. Massagute; argues. "By comparison, the changes in gene expression responsible for the phenotypic differences observed between tumorigenic breast cancer cells and nontumorigenic breast cancer cells may not be extensive."

N Engl J Med 2007;356:217-226, 294.

    
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