In a finding that vastly expands the understanding of tumor evolution, researchers discover genetic biomarkers that can predict the breast cancer subtype a patient is likely to develop.

在一項大為擴展了，瞭解腫瘤演化的發現中。研究人員們發現了，能預測病患可能罹患之乳癌亞型的遺傳生物標記物。

圖1. 美國史丹佛大學醫學院，研究人員們發現，遺傳基因序列可以預測患者，可能罹患哪種類型的乳癌，及癌腫會是多具侵犯性。

Stanford Medicine researchers found that inherited gene sequences can predict what type of breast cancer a patient is likely to develop, along with how aggressive that cancer may be.  

A Stanford Medicine study of thousands of breast cancers has found that the gene sequences we inherit at conception are powerful predictors of the breast cancer type we might develop decades later and how deadly it might be.

一項美國史丹佛大學醫學院，有關數千件乳癌的研究業已發現，我們在受孕時，承襲的基因序列，是我們數十年後，可能罹患及其會是多致命之乳癌類型的強有力預測物。

The study challenges the dogma that most cancers arise as the result of random mutations that accumulate during our lifetimes. Instead, it points to the active involvement of gene sequences we inherit from our parents — what’s known as your germline genome — in determining whether cells bearing potential cancer-causing mutations are recognized and eliminated by the immune system or skitter under the radar to become nascent cancers. 

這項研究挑戰了，在確定是否細胞懷有，由免疫系統識別及消除，或在此探測系統下掠過，成為新生癌腫之潛在致癌的突變體上，大多數癌腫起因於，我們一生中，累積之隨機突變結果的理論。而是，朝向我們從父母承襲之基因序列(即所謂的種系基因體)的積極涉及。

“Apart from a few highly penetrant genes that confer significant cancer risk, the role of hereditary factors remains poorly understood, and most malignancies are assumed to result from random errors during cell division or bad luck,” said Christina Curtis, PhD, the RZ Cao Professor of Medicine and a professor of genetics and of biomedical data science.

醫學的RZ Cao教授兼遺傳學暨生物醫學數據科學教授的Christina Curtis 博士宣稱：「除了一些帶來重大癌腫風險的高度具滲透力基因之外，遺傳因素的角色，仍然未充分被瞭解。大多數惡性腫瘤被認為，起因於細胞分裂過程中的隨機出錯，或運氣不佳。

This would imply that tumor initiation is random, but that is not what we observe. Rather, we find that the path to tumor development is constrained by hereditary factors and immunity. This new result unearths a new class of biomarkers to forecast tumor progression and an entirely new way of understanding breast cancer origins.”

這可能暗示，腫瘤的發生是隨機的。不過，那不是我們所觀察到的。而是，我們發現，腫瘤發展途徑遭到遺傳因素及免疫力的抑制。此新結果揭露了一種，預測腫瘤發展，及瞭解乳癌起源之全新方法的生物標記。

Curtis is the senior author of the study, which will be published May 31 in Science. Postdoctoral scholar Kathleen Houlahan, PhD, is the lead author of the research.

Curtis是該項，將在(2024年)5月31日發表於《科學》雜誌的研究資深撰文人。博士後學者Kathleen Houlahan博士，是這項研究的首要撰文人。

“Back in 2015, we had posited that some tumors are ‘born to be bad’ — meaning that their malignant and even metastatic potential is determined early in the disease course,” Curtis said. “We and others have since corroborated this finding across multiple tumors, but these findings cast a whole new light on just how early this happens.”

Curtis宣稱：「於2015年，我們曾假設有些腫瘤‘生來就是劣質’。意味著，其惡性、甚至轉移的潛力，在病程初期就已確定。此後，在跨多種腫瘤上，我們及其他人已經證實此發現。不過，此些研究發現，僅將一種全新的見解施於，此發生於多早期。」

The study, which gives a nuanced and powerful new understanding of the interplay between newly arisen cancer cells and the immune system, is likely to help researchers and clinicians better predict and combat breast tumors.

這項提供有關，在新出現的癌細胞與免疫系統間相互作用，細緻入微且強有力之新理解的研究，很可能有助於研究人員及臨床醫生們，更佳預測及對抗乳房腫瘤。

Currently, only a few high-profile cancer-associated mutations in genes are regularly used to predict cancers, but these account for a small minority of cases. Those include BRCA1 and BRCA2, which occur in about one of every 500 women and confer an increased risk of breast or ovarian cancer, and rarer mutations in a gene called TP53 that causes a disease called Li Fraumeni syndrome, which predisposes to childhood and adult-onset tumors.

目前，於基因中，僅少數引人注目之與癌腫相關的突變，正式被用於預測癌腫。不過，這些占少數病例。那些包括，發生於大約1/500名女性中，且帶來增加乳癌或卵巢癌風險的BRCA1及BRCA2，及在一種被稱為TP53基因中，引發一種被稱為Li Fraumeni症候群的疾病。這種疾病容易傾向是兒童時期及成人發病的腫瘤。

The findings suggest there are tens or hundreds of additional gene variants — identifiable in healthy people — that through interactions with the immune system pull the strings that determine why some people remain cancer-free throughout their lives.

此些研究發現暗示，有數十或數百種，透過與免疫系統的交互作用，暗中操縱，決定為何有些人，終生保持免於癌腫的額外基因變異體。

“Our findings not only explain which subtype of breast cancer an individual is likely to develop,” Houlahan said, “but they also hint at how aggressive and prone to metastasizing that subtype will be. Beyond that, we speculate that these inherited variants may influence a person’s risk of developing breast cancer. However, future studies will be needed to examine this.”

Houlahan宣稱：「我們的此些研究發現，不僅解釋個體很可能罹患哪種乳癌亞型，而且它們也透露，那種亞型會是多具侵犯性及多易於轉移。除此之外，我們推測，此些遺傳的變異會影響，一個人罹患乳癌的風險。不過，將需要諸多未來的研究，來檢驗此推測。」

The genes we inherit from our parents are known as our germline genome. They’re mirrors of our parents’ genetic makeup, and they can vary among people in small ways that give some of us blue eyes, brown hair or type O blood. Some inherited genes include mutations that confer increased cancer risk from the get-go, such as BRCA1, BRCA2 and TP53.

此些我們遺傳自咱們雙親，被通稱為咱們的種系基因體。它們是咱們雙親基因的組成鏡子，因此它們在人與人之間，會在使我們一些人，具有藍眼睛、棕色頭髮或O型血的諸多小方面，呈現差異。一些遺傳的基因包括，從一開始就帶來，增加癌腫風險的突變，諸如BRCA1、BRCA2 及TP53。

In contrast, most cancer-associated genes are part of what’s known as our somatic genome. As we live our lives, our cells divide and die in the tens of millions. Each time the DNA in a cell is copied, mistakes happen and mutations can accumulate. DNA in tumors is often compared with the germline genomes in blood or normal tissues in an individual to pinpoint which changes likely led to the cell’s cancerous transformation.

相較之下，大多數與癌腫相關的基因，是被通稱為咱們體細胞基因體的一部分。於細胞中，每一次DNA被複製，會發生錯誤且會累積突變體。於腫瘤中的DNA往往，與個體之血液或正常組織中的種系基因體進行比較，以精確找出哪些變化，很可能導致細胞的癌變。

In 2012, Curtis began a deep dive — assisted by machine learning — into the types of somatic mutations that occur in thousands of breast cancers. She was eventually able to categorize the disease into 11 subtypes with varying prognoses and risk of recurrence, finding that four of the 11 groups were significantly more likely to recur even 10 or 20 years after diagnosis — critical information for clinicians making treatment decisions and discussing long-term prognoses with their patients.

於2012 年，由機器學習協助下，Curtis開始深入研究，於數千件乳癌中，發生的體細胞突變類型。最終，她能將這種疾病分成11種，具有不同預後(一種醫學名詞，指根據病人當前狀況，來推估未來經過治療後可能的結果)及復發風險的亞型，且發現其中四群，顯著較可能甚至，在診斷後10或20年復發。對做出治療決策並與其患者討論長期預後的臨床醫生而言，這是不可或缺的資訊。

Prior studies had shown that people with inherited BRCA1 mutations tend to develop a subtype of breast cancer known as triple negative breast cancer. This correlation implies some behind-the-scenes shenanigans by the germline genome that affects what subtype of breast cancer someone might develop.

先前諸多研究已經證實，具有遺傳之BRCA1突變的人，傾向於罹患一種，被通稱為三陰性乳癌的乳癌亞型。此相關性意味著，一些由種系基因體影響，有人可能罹患哪種乳癌亞型的幕後狡猾伎倆。

“We wanted to understand how inherited DNA might sculpt how a tumor evolves,” Houlahan said. To do so, they took a close look at the immune system.

It’s a quirk of biology that even healthy cells routinely decorate their outer membranes with small chunks of the proteins they have bobbing in their cytoplasm — an outward display that reflects their inner style.

Houlahan宣稱：「我們想瞭解，遺傳的DNA如何能影響，腫瘤如何演變。」為此，她們仔細研究了免疫系統。這是，即使健康細胞也例行使用，在其細胞質中，具有快速擺動的小塊蛋白質，來裝飾其外膜。這是一種，反映其內部樣式的向外展示。

The foundations for this display are what’s known as HLA proteins, and they are highly variable among individuals. Like fashion police, immune cells called T cells prowl the body looking for any suspicious or overly flashy bling (called epitopes) that might signal something is amiss inside the cell. A cell infected with a virus will display bits of viral proteins; a sick or cancerous cell will adorn itself with abnormal proteins. These faux pas trigger the T cells to destroy the offenders.

此展示的基礎是，在個體之間高度可變，被通稱為人類白血球抗原( HLA：human leukocyte antigen )的蛋白。像時尚警察一樣，被稱為T細胞的免疫細胞，在體內徘徊，尋找於細胞內，可能以信號告知某事出了差錯之任何可疑或過於閃爍的亮光(被稱為抗原表位：抗原分子上與抗體或淋巴細胞受體結合的部位)。感染病毒的細胞會展示出，一些病毒蛋白；患病或癌變的細胞，會以異常蛋白質裝飾自己。此些失常行為觸發T細胞，來消滅這些惹人不適之物。

Houlahan and Curtis decided to focus on oncogenes, normal genes that, when mutated, can free a cell from regulatory pathways meant to keep it on the straight and narrow.

Houlahan及Curtis決定著重於，當正常基因發生突變時，能使細胞免於，必須保持其處於正確且精密之調節途徑的致癌基因。

Often, these mutations take the form of multiple copies of the normal gene, arranged nose to tail along the DNA — the result of a kind of genomic stutter called amplification. Amplifications in specific oncogenes drive different cancer pathways and were used to differentiate one breast cancer subtype from another in Curtis’ original studies.

通常，此些突變以正常基因，多個複製的形式出現，沿著DNA從頭到尾排列。這是一種，被稱為擴大之基因體結巴狀的結果。於特異性致癌基因中的擴大，驅動不同的癌腫途徑。因此，在Curtis的原始研究中，被用來區別乳癌的諸亞型。

The researchers wondered whether highly recognizable epitopes would be more likely to attract T cells’ attention than other, more modest displays (think golf-ball-sized, dangly turquoise earrings versus a simple silver stud).

此些研究人員想知道，是否高度可識別的抗原表位，更有可能吸引T細胞注意(想想高爾夫球大小、晃動的綠松石耳環與簡單的銀耳釘)，更適中的展示。

If so, a cell that had inherited a flashy version of an oncogene might be less able to pull off its amplification without alerting the immune system than a cell with a more modest version of the same gene.

倘若如此，具有承襲了暴躁版致癌基因的細胞，或許比具有相同基因之較溫和版的細胞，較不能沒有引起免疫系統警覺，而獲致其擴大。

The researchers studied nearly 6,000 breast tumors spanning various stages of disease to learn whether the subtype of each tumor correlated with the patients’ germline oncogene sequences.

此些研究人員研究了，近6千件跨越不同疾病階段的乳房腫瘤，以獲悉每種腫瘤的亞型，是否與病患的種系致癌基因序列相關聯。

They found that people who had inherited an oncogene with a high germline epitope burden (read: lots of bling) — and an HLA type that can display that epitope prominently — were significantly less likely to develop breast cancer subtypes in which that oncogene is amplified.

她們發現，承襲了具有高種系抗原表位負荷(內容是：大量亮光)的致癌基因，及承襲了能顯著展示抗原表位之人類白血球抗原(HLA：Human Leukocyte Antigen)類型的人，顯著較不可能罹患，致癌基因被擴大的乳癌亞型。

There was a surprise, though. The researchers found that cancers with a large germline epitope burden that manage to escape the roving immune cells early in their development tended to be more aggressive and have a poorer prognosis than their more subdued peers.

不過，有項令人驚訝之事。此些研究人員發現，在其發展初期，具有大量設法逃脫流動的免疫細胞之種系抗原表位負荷的癌腫，傾向更具侵犯性，且具有比其較被抑制的同等癌腫，更不佳的預後。

“At the early, pre-invasive stage, a high germline epitope burden is protective against cancer,” Houlahan said. “But once it’s been forced to wrestle with the immune system and come up with mechanisms to overcome it, tumors with high germline epitope burden are more aggressive and prone to metastasis. The pattern flips during tumor progression.”

Houlahan宣稱：「於初期、侵犯前的階段，高種系抗原表位負荷，是具防禦癌腫的。不過，一旦它已被迫與免疫系統搏鬥，並想出克服它的機制。具有高種系抗原表位負荷的腫瘤，更具侵犯性且易於轉移。在腫瘤發展過程中，此模式發生翻轉。」

“Basically, there is a tug of war between tumor and immune cells,” Curtis said. “In the preinvasive setting, the nascent tumor may initially be more susceptible to immune surveillance and destruction. Indeed, many tumors are likely eliminated in this manner and go unnoticed.

Curtis宣稱：「基本上，在腫瘤與免疫細胞之間，有一場強大較量的戰爭。在侵犯前的環境中，新生腫瘤最初可能較易遭到免疫監視及摧毀。實際上，諸多腫瘤很可能，以此方式被消除，而不被注意到。

However, the immune system does not always win. Some tumor cells may not be eliminated and those that persist develop ways to evade immune recognition and destruction. Our findings shed light on this opaque process and may inform the optimal timing of therapeutic intervention, as well as how to make an immunologically cold tumor become hot, rendering it more sensitive to therapy.”

然而，免疫系統並非總是獲勝。有些腫瘤細胞可能不被消除，而那些持續存在的腫瘤細胞發展出，諸多規避免疫辨識及摧毀的方法。我們的此些研究發現，除了如何使免疫上難以抑制的腫瘤變成非常有力，使其對治療更加敏感之外，也闡明了此難以瞭解之過程，且可能告知治療幹預的最佳時機。」

The researchers envision a future when the germline genome is used to further stratify the 11 breast cancer subtypes identified by Curtis to guide treatment decisions and improve prognoses and monitoring for recurrence. The study’s findings may also give additional clues in the hunt for personalized cancer immunotherapies and may enable clinicians to one day predict a healthy person’s risk of developing an invasive breast cancer from a simple blood sample.

當此種系基因體被Curtis用來進一步分層，由Curtis確認的11種乳癌亞型時，這些研究人員展望一項，引導治療決策及改善預後及監測復發的願景。該項研究的諸多發現，在尋找個人化癌症免疫療法上，也可能提供額外的線索且有朝一日，可能使臨床醫生們能從簡單的血液樣本，預測健康人罹患侵犯性乳癌的風險。

“We started with a bold hypothesis,” Curtis said. “The field had not thought about tumor origins and evolution in this way. We’re examining other cancers through this new lens of hereditary and acquired factors and tumor-immune co-evolution.”

Curtis宣稱：「我們以一種大膽的假設開始。該領域未曾以這種方式，思考腫瘤的起源及發展。我們正透過遺傳性及後天性因素，及腫瘤與免疫共同發展的新透鏡，來檢查其他癌腫。」

The study was funded by the National Institutes of Health, the Canadian Institutes of Health Research and the Chan Zuckerberg Biohub.

該項研究是由，美國國家衛生研究院、加拿大衛生研究院及Chan Zuckerberg生物中心所資助。

網址：https://med.stanford.edu/news/all-news/2024/05/genes-breast-cancer.html

翻譯：許東榮