基因变异筛查预测乳腺癌风险

A massive study of nearly 4,000 variants in a gene associated with cancer could help to pinpoint people at risk for breast or ovarian tumours.

一项对近4000个与癌症相关的基因变异进行的大规模研究，可能有助于查明有患乳腺癌或卵巢癌风险的人群。

The information is sorely needed: millions of people have had their BRCA1 gene sequenced.

人们迫切需要这些信息:数以百万计的人已经对自己的BRCA1基因进行了测序。

Some variations in the DNA sequence of BRCA1 are linked to breast and ovarian cancer; others are thought to be safe.

BRCA1 DNA序列的某些变异与乳腺癌和卵巢癌有关;其他的则被认为是安全的。

But the effects of most variants are unknown, leaving patients and physicians alike at a loss to interpret the results.

但是大多数变异的影响是未知的，这使得病人和医生都无法预测其结果。

The study, published on 12 September in Nature1, examined the effects of thousands of such variants on the survival of cells grown in the laboratory.

这项研究发表在9月12日的《自然》杂志上，研究了成千上万的这种变异对实验室中生长的细胞的存活率的影响。

The findings could help physicians to interpret the mutations’ significance.

这些发现可以帮助医生解释突变的意义。

For example, a variant that hampers a cell’s ability to repair DNA in the lab might also be linked to cancer in the clinic.

例如，在实验室中阻碍细胞修复DNA能力的变异也可能与临床癌症有关。

“Every patient is different. Every physician is different,” says Jay Shendure, a geneticist at the Brotman Baty Institute for Precision Medicine in Seattle, Washington, and a co-author of the study.

“每个病人都是不同的。每个医生也是不同的，”杰.辛杰说道，他是华盛顿州西雅图市的Brotman Baty精密医学研究所的一名遗传学家，也是这项研究的共同作者。

“But if such a variant were present in a family member of mine, would I use this information? Absolutely. Otherwise, there’s no information.”

“但假如我的某个家庭成员中出现了这种变异，那么我可以借鉴这个信息吗？肯定可以。要不然，就没什么信息可借鉴了。”

The American College of Medical Genetics and Genomics recognizes about 60 genes for which screening might suggest a medical plan to preventor reduce the effects of a disease.

美国医学遗传学和基因组学学院承认了大约60种基因，这些基因的筛选可能可以为医学计划提供建议来预防或减少疾病的影响。

Yet often when people find out that their genes include unusual DNA sequences , they are at a loss to interpret that finding.

然而，通常情况下，当人们发现他们的基因包含了不寻常的DNA序列时，他们却无法解释这一发现。

“These variants are nightmarish,” says Alvaro Monteiro, a geneticist at the Moffitt Cancer Center in Tampa, Florida.

“这些变异是梦魇般的，”佛罗里达坦帕莫菲特癌症中心的遗传学家阿尔瓦罗·蒙泰罗说。

“The result becomes: 'Well, you have something, but we just don’t know exactly what it is.’”

“结果就变成了:'嗯，你有一些变异，但我们却不知道它到底是什么。’”

Assays for genetic causes of hearing loss are a prime example: about half of the people who undergo such testing find out that they carry variants whose significance is unknown, says Heidi Rehm, a geneticist at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.

听力损失的遗传原因分析就是一个很好的例子:大约有一半的人接受了这样的测试，他们发现自己携带的变异基因的意义不明，海蒂.雷姆说道，她是马萨诸塞州的剑桥市的麻省理工和哈佛的布罗德研究所的一名遗传学家。

“It’s a definite challenge in all genetic testing areas,” she says.

“在所有的基因检测领域，这都是一个明确的挑战，”她说道。

For BRCA1, the stakes are particularly high: women whose BRCA1 sequence puts them at risk for cancer will sometimes have surgery to remove their breasts and ovaries.

对于BRCA1来说，风险尤其高:那些BRCA1基因序列有癌症风险的女性，有时会进行切除乳房和卵巢的手术。

Rehm says that there are more than 2,500 known variants of uncertain significance in BRCA1.

雷姆说，在BRCA1中有超过2500个已知的不确定意义的变体。

Shendure and fellow Brotman Baty Institute geneticist Lea Starita decided to tackle this problem using cells that die without a functioning BRCA1 protein, which is important for DNA repair.

辛杰和Brotman Baty研究所的基因学家Lea Starita决定使用基因BRCA1蛋白缺失的细胞来解决这个问题，这种蛋白对基因修复很重要。

They used CRISPR–Cas9 gene editing to create mutations throughout the BRCA1 gene, and then looked to see which of the resulting cells survived.

他们使用CRISPR-Cas9基因编辑技术在BRCA1基因中创造突变，然后观察结果中哪些细胞存活了下来。

The screen covered nearly every possible single-letter variation in regions of BRCA1 known to be important for the function of its associated protein.

这次筛选覆盖了BRCA1区域中几乎所有可能的单碱基变异，已知这些区域对相关蛋白的功能至关重要。

In cases where clinical data were available, lab results correlated with clinical findings more than 96% of the time.

在有临床数据的病例中，实验室结果与临床结果相关性超过96%。

The approach could be expanded to some other disease-related genes, particularly cancer-associated genes that are important for DNA repair, says Monteiro.

蒙特罗说，这种方法可以扩展到其他一些疾病相关基因，特别是对DNA修复很重要的癌症相关基因。

Ideally, these data would be combined with other genetic information about a given variant, but more data might not be available for rare sequences.

理想情况下，这些数据将与关于某个特定变体的其他遗传信息相结合，但对于罕见的序列，可能无法获得更多的数据。

In such cases, it will be up to the patient and their physician to decide how to interpret the results, says Starita.

斯塔利塔说，在这种情况下，只有靠病人和他们的医生来决定如何解释结果。

Some might choose to conduct further screening for cancer, in an effort to catch tumours early, she notes.

她指出，有些人可能会选择进行进一步的癌症筛查，以便尽早发现肿瘤。

And eventually, researchers might incorporate lab results, such as those derived from the CRISPR screen, directly into the models they use to classify variants , Monteiro says.

最终，研究人员可能会将实验室的结果，比如CRISPR筛选的结果，直接整合到他们用来对变异归类的模型中去，蒙特罗说道。

But he also notes that the field tends to be conservative, and will likely require more evidence before it makes the change.

但他也指出，该领域趋于保守，可能需要更多证据才能做出改变。

“This is a very thorny subject,” he says.

“这是一个很棘手的问题，”他说道。

“When we try once to classify a variant, we really like that decision to never change again.”

“当我们试着把一个变种分类时，我们真的很希望这个决定:永远不再改变。”

doi: 10.1038/d41586-018-06665-x

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