發現罕見兒童癌癥的起源可以指導治療

時間：2021-02-22  來自：盛諾一家 返回上頁

新的研究表明，患者體內的雙側神經母細胞瘤可以彼此獨立地發生。這類腫瘤尚未從一個部位擴散（轉移）到另一個部位，這一發現對理解神經母細胞瘤的根源具有重要意義，并可能促進更好的治療。

來自Wellcome Sanger研究所、劍橋大學、劍橋大學醫院、大奧蒙德街兒童醫院和倫敦大學學院大奧蒙德街兒童健康研究所的研究人員研究了兩名患者多個部位的腫瘤基因組。在這兩個病例里，患者體內的腫瘤都是獨立發生的，它們的起源都是在胚胎發育階段。發表在今天(11月4日)的《新英格蘭醫學雜志》上的研究結果可能與治療其它類型的雙側腫瘤有關。

神經母細胞瘤是一種高度侵襲性的兒童癌癥。在英國，每年大約有100名兒童受到影響。它是由胎兒在子宮發育過程中遺留下來的特化神經細胞——成神經細胞發展而來的。

神經母細胞瘤最常見于腎臟上方的一個腎上腺。神經母細胞瘤有幾種不同的類型，有些更具侵襲性。在罕見的病例中會發生雙側腫瘤，例如在雙側腎上腺中。

與物種的進化相似，人體內的單個細胞在成長過程中也會受到變異和選擇的影響。這些“體細胞突變”在細胞分裂時從一個細胞傳遞到另一個細胞。在一生中，不同的突變會在不同細胞的DNA中積累。通過比較腫瘤細胞和健康細胞之間的體細胞突變模式，就有可能追蹤它們的進化歷史。

在這項新的研究中，Wellcome Sanger研究所的研究人員對雙側神經母細胞瘤進行了廣泛的基因組測序。進化基因組學表明，個體的神經母細胞瘤腫瘤是在生命的最早期階段獨立受精后出現的。研究中的兩個孩子都遺傳了一種使他們容易患癌癥的基因突變。

“由于測序技術的進步和分析方法的發展，最近將兒童癌癥的起源追溯到胚胎已經成為可能。這是我們對腫瘤的看法以及它們在成為腫瘤之前如何相互聯系的范式轉變。獨立腫瘤的平行進化是一個意想不到的有趣發現，它揭示了神經母細胞瘤的起源于受精卵的最初幾次分裂?！?/p>

——Wellcome Sanger研究所的Tim Coorens，該研究的第一作者

了解病人體內的腫瘤是否獨立是臨床醫生在決定最佳治療方案時的重要信息。通常認為多發部位的腫瘤是從原發腫瘤擴散而來的轉移性疾病。與保留在組織微環境中的腫瘤相比，已經從一個部位轉移并擴散到另一個部位的腫瘤更具侵略性，并且需要更多的強化治療。

“這是我們第一次能夠證明雙側神經母細胞瘤腫瘤可以是獨立的實體。對于每個病人來說，臨床醫生能夠區分正在擴散的侵襲性腫瘤和一組局部的良性腫瘤是非常重要的。如果腫瘤沒有轉移，我們可以考慮減少強化治療，減少副作用?！?/p>

——John Anderson，敦大學學院大奧蒙德街兒童健康研究所和大奧蒙德街兒童醫院教授，該研究論文的作者。

研究人員猜測其它類型的雙側腫瘤可能也有類似的發展模式，因此他們的發現對于分析和治療這類癌癥具有更廣泛的重要意義。

“神經母細胞瘤是最常見的兒童腫瘤之一，英國每年約有100名兒童被診斷為神經母細胞瘤。然而，它的存活率也是最低的——在高風險的情況下，存活率只有50%左右?！?/p>

“我們歡迎這些發現，因為這是朝著開發針對神經母細胞瘤患兒更友好、更安全、更個性化的治療邁出的重要一步，這將有助于減少當前積極治療的長期且通常會限制生命的副作用?！?/p>

——Dr. Jasmine Parkinson，英國兒童癌癥研究與贈款經理

“我們現在所處的世界中，腫瘤基因組測序是醫療保健的一部分。它正在成為臨床上治療兒童癌癥的重要工具。利用基因組學分析腫瘤的起源可以使我們對正在處理的疾病以及如何解決它有更深入的了解?！?/p>

——Dr. Sam Behjati，論文的主要作者

Uncovering the origin of rare childhood cancer guides treatment 

4 November 2020

Bilateral neuroblastoma cancers in a patient can arise independently from each other, at the very earliest stages of life

New research shows that bilateral neuroblastoma cancers within a patient can arise independently from each other. The finding that such tumours have not spread – metastasised – from one site to another has important implications for understanding the roots of neuroblastoma and may promote better treatments.

Researchers from the Wellcome Sanger Institute, the University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, Great Ormond Street Hospital for Children NHS Trust and the UCL Great Ormond Street Institute of Child Health studied the genomes of tumours from multiple sites in two patients with the condition. In both cases the tumours within a patient arose separately from each other, with their origins in embryonic development. Their findings, published in the New England Journal of Medicine today, 4th November, may be relevant for treating other types of bilateral tumours.

Neuroblastoma is a highly aggressive childhood cancer. About 100 children each year in the UK are affected. It develops from specialised nerve cells – neuroblasts – left behind from a baby’s development in the womb*.

Neuroblastoma most commonly occurs in one of the adrenal glands above the kidneys. There are several different types of neuroblastoma, with some more aggressive than others. In rare cases, bilateral tumours occur, for example in both adrenal glands.

Similarly to the evolution of species, individual cells in the body are subject to forces of mutation and selection as they grow. These ‘somatic mutations’ are passed from one cell to another as it divides**. Over a lifetime, different mutations accumulate in the DNA of different cells. By comparing the patterns of somatic mutations between tumour cells and healthy cells, it is possible to trace their evolutionary history.

In this new study, researchers at the Wellcome Sanger Institute extensively sequenced the genomes of bilateral neuroblastoma. Evolutionary genomics showed that the neuroblastoma tumours in an individual arose independently at the very earliest stages of life, within a few cell divisions after fertilization. Both children in the study had inherited a genetic mutation that predisposed them to cancer.

“Thanks to advances in sequencing technologies and developments in analysis methods, it has recently become possible to trace the origin of childhood cancer right back to the embryo. It’s a paradigm shift in how we think about tumours, and how they are related to each other before they became tumours. The parallel evolution of independent tumours was an unexpected and fascinating finding, which reveals the very origin of neuroblastoma within the first few divisions of the fertilised egg.”

Tim Coorens,first author of the study from the Wellcome Sanger Institute

Understanding if tumours within a patient are independent or not is vital information for clinicians when deciding the best treatment options. It is usually assumed that tumours at multiple sites are metastatic disease that spread from an original primary tumour. A tumour that has metastasised and spread from one site to another is more aggressive – and requires more intensive treatment – than one that remains within a tissue microenvironment.

“This is the first time we’ve been able to prove that bilateral neuroblastoma tumours can be independent entities. It is essential for each patient that clinicians can make the distinction between an aggressive tumour that is spreading, and a set of more benign tumours that are localised. If tumours haven’t metastasised, we can consider less intensive treatments, with fewer side effects.”

Professor John Anderson,senior author of the study from the UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust

The researchers suspect that other types of bilateral tumours may also have similar patterns of development, and so their findings are important more widely for analysing and treating such cancers.

“Neuroblastoma is one of the most common childhood tumours with around 100 children diagnosed in the UK each year. Yet, it also has one of the lowest survival rates – in its high-risk form, the survival rate is sadly around just 50 per cent.

“We welcome these findings as an important step towards the development of kinder, safer, and more personalised, treatments for children with neuroblastoma which will help reduce the long-term, and often life-limiting, side effects of current aggressive treatments.”

Dr Jasmine Parkinson,Children with Cancer UK Research and Grants Manager

“We are in a world now where genome sequencing tumours is a part of healthcare. It is becoming an important tool in the clinic for treating childhood cancers. Using genomics to analyse a tumour’s origins can give us detailed insight into what we are dealing with and how to tackle it.”

Dr Sam Behjati,lead author of the study from the Wellcome Sanger Institute and Addenbrooke’s Hospital, Cambridge

本文編譯自UCL大奧蒙德街兒童健康研究所官網于2020年11月4日發表的《發現罕見兒童癌癥的起源可以指導治療》，Uncovering the origin of rare childhood cancer guides treatment ，from: https://www.ucl.ac.uk/child-health/news/2020/nov/uncovering-origin-rare-childhood-cancer-guides-treatment