Open Osmosis

翻译：润子

A 39-year-old woman comes to the office for an annual examination. She is concerned about her risk of developing breast and ovarian cancer given her strong family history. She decides to get tested for BRCA1 and BRCA2 mutations. Which of the following best describes how mutations in these genes lead to cancer?

一位39岁的女性前来医院做她的年度体检。因为有明确的家族史，她非常担心自己有患乳腺癌和卵巢癌的风险。她决定检测BRCA1和BRCA2基因是否存在突变。以下对于这两个基因的突变是如何导致癌症的描述中，哪一项最准确？

A. Repression of a tumor suppressor gene 抑癌基因的基因抑制 B. Gain of function of an oncogene 癌基因的功能获得 C. Gain of function of tumor suppressor gene 抑癌基因的功能获得 D. Loss of function of a tumor suppressor gene 抑癌基因的功能缺失 E. Loss of function of an oncogene 癌基因的功能缺失

Answer 解析

感觉这是一道考BRCA1和BRCA2这两个基因的常识题。首先，BRCA1和BRCA2是两个著名的抑癌基因，而不是癌基因，可以排除B、E。其次，如果是抑癌基因的功能获得的话，根本不可能导致癌症吧= =，所以排除C。然后就在A、E之间纠结一下，而Repression（基因抑制）和Loss of function（功能缺失）是完全不同的概念，详情正确答案详解。

A. Repression of a tumor suppressor gene抑癌基因的基因抑制

Methylation is a means of epigenetic regulation and is usually associated with repressed gene transcription. However, this is not the mechanism by which BRCA1 and BRCA2 contribute to cancer development.

基因的甲基化是表观遗传调节的一种方式，主要与基因转录抑制相关。甲基化程度高的基因往往被沉默。然而这并不是BRCA1、BRCA2这两个抑癌基因导致癌症的方式。

B. Gain of function of an oncogene癌基因的功能获得

Oncogenes are overexpressed or mutated in tumor cells. Activated oncogenes induce survival and proliferation in cells that would usually undergo apoptosis. However, BRCA1 and BRCA2 genes are not oncogenes.

在肿瘤细胞中，癌基因要么过表达，要么发生突变。激活的癌基因会导致本来应该凋亡的细胞的持续存活和增殖。这的确肿瘤发生的重要机制之一，但BRCA1、BRCA2这两个基因并不是癌基因。

C. Gain of function of tumor suppressor gene抑癌基因的功能获得

As their name suggests, the function of tumor suppressor genes have a repressive effect in the cancer development sequence. According to the "two-hit hypothesis," both alleles of the tumor suppressor gene must be mutated for the cancer to develop.

顾名思义，抑癌基因的功能获得可以抑制肿瘤的发展。根据“二次突变假说”，只有抑癌基因的两个等位基因位点都发生突变，才会导致癌症的发生。

D. Loss of function of a tumor suppressor gene抑癌基因的功能缺失

此为正确答案。详情见下。

E. Loss of function of an oncogene癌基因的功能缺失

Oncogenes are overexpressed or mutated in tumor cells. Activated oncogenes induce survival and proliferation in cells that would usually undergo apoptosis.

在癌症细胞中，癌基因往往发生过表达或突变。激活的癌基因会导致本来应该凋亡的细胞的持续存活和增殖。（把B选项又重新说了一遍）。

Main Explanation

正确答案详解

Tumor suppressor genes are responsible for suppressing uncontrolled growth. Therefore, a loss-of-function mutation in tumor suppressor genes leads to uncontrolled cell growth and proliferation which can progress to dysplasia and cancer. 

Tumor suppressors alleles are considered recessive because if there is mutated allele, the second one can still produce the normal protein (there are some notable exceptions to this rule, such as p53, a tumor suppressor gene that has a dominant negative, and NF1, which exhibits haploinsufficiency). By contrast, oncogene alleles are typically dominant.

如果把癌症看成一场细胞的疯狂增殖，那抑癌基因的职责就是镇压不受控制的细胞生长。因此，如果抑癌基因发生“功能缺失性突变”，将会导致细胞不受控制地生长、增殖，发展为不典型增生，甚至癌症。通常，抑癌基因的两个等位基因位点符合隐性遗传定律，因为如果第一个等位基因位点突变掉了，第二个等位基因位点仍能转录翻译产生正常的蛋白质。

不过，有一些基因并不遵循这一规律，比如著名的抑癌基因p53符合显性遗传定律（即一个位点突变即无法发挥正常功能。还有NF1基因，存在“单倍剂量不足”的现象，指一个等位基因突变后，另一个等位基因随能正常表达，但相当于正常水平50%的蛋白质量不足以维持细胞的正常生理功能。与抑癌基因的隐性遗传形成对比的是癌基因的等位基因位点，通常遵循显性遗传定律。

The person described here is Angelina Jolie, who tested positive for BRCA1. She has a strong family history of breast and ovarian cancer. Her mother was diagnosed with ovarian cancer at 49 years old and passed away. BRCA1 and BRCA2 are tumor suppressor genes involved in repairing damaged DNA. 

On March 24, 2015, she wrote in the New York Times: "A simple blood test had revealed that I carried a mutation in the BRCA1 gene. It gave me an estimated 87 percent risk of breast cancer and a 50 percent risk of ovarian cancer. I lost my mother, grandmother and aunt to cancer." Jolie subsequently underwent a bilateral mastectomy as well as bilateral salpingo-oopherectomy.

其实，这个案例中的这位女士就是美国影星安吉丽娜·朱莉，她被检出携带BRCA1基因突变。朱莉有确凿的乳腺癌及卵巢癌家族史：母亲49岁时确诊患有卵巢癌，并因此去世。BRCA1和BRCA2是参与损伤DNA修复的抑癌基因。

2015年3月24日，她在《纽约时报》中这样写道：“只是一次简单的血液检查，我被告知携带BRCA1基因突变。这简单的一个基因突变就导致我有87%的几率罹患乳腺癌，50%的几率罹患卵巢癌。因为癌症，我已经失去了我的母亲、我的祖母以及我的阿姨。”因此，朱莉接受了双侧乳房切除手术，以及双侧输卵管卵巢切除术，从而将罹患癌症的风险降低到了5%以下。

安吉丽娜朱莉之所以将她的就诊经历、所有手术细节以及感受公开发表于纽约时报，是为了唤起更多女性的癌症基因筛查意识，引起了广泛的“安吉丽娜·朱莉效应”。

她的这篇纽约时报文章《My Medical Choice》全文如下，译者：李潇。

My Medical Choice

By ANGELINA JOLIE / MAY 14, 2013

Angelina Jolie

MY MOTHER fought cancer for almost a decade and died at 56. She held out long enough to meet the first of her grandchildren and to hold them in her arms. But my other children will never have the chance to know her and experience how loving and gracious she was.

We often speak of “Mommy’s mommy,” and I find myself trying to explain the illness that took her away from us. They have asked if the same could happen to me. I have always told them not to worry, but the truth is I carry a “faulty” gene, BRCA1, which sharply increases my risk of developing breast cancer and ovarian cancer.

My doctors estimated that I had an 87 percent risk of breast cancer and a 50 percent risk of ovarian cancer, although the risk is different in the case of each woman.

Only a fraction of breast cancers result from an inherited gene mutation. Those with a defect in BRCA1 have a 65 percent risk of getting it, on average.

Once I knew that this was my reality, I decided to be proactive and to minimize the risk as much I could. I made a decision to have a preventive double mastectomy. I started with the breasts, as my risk of breast cancer is higher than my risk of ovarian cancer, and the surgery is more complex.

On April 27, I finished the three months of medical procedures that the mastectomies involved. During that time I have been able to keep this private and to carry on with my work.

But I am writing about it now because I hope that other women can benefit from my experience. Cancer is still a word that strikes fear into people’s hearts, producing a deep sense of powerlessness. But today it is possible to find out through a blood test whether you are highly susceptible to breast and ovarian cancer, and then take action.

My own process began on Feb. 2 with a procedure known as a “nipple delay,” which rules out disease in the breast ducts behind the nipple and draws extra blood flow to the area. This causes some pain and a lot of bruising, but it increases the chance of saving the nipple.

Two weeks later I had the major surgery, where the breast tissue is removed and temporary fillers are put in place. The operation can take eight hours. You wake up with drain tubes and expanders in your breasts. It does feel like a scene out of a science-fiction film. But days after surgery you can be back to a normal life.

Nine weeks later, the final surgery is completed with the reconstruction of the breasts with an implant. There have been many advances in this procedure in the last few years, and the results can be beautiful.

I wanted to write this to tell other women that the decision to have a mastectomy was not easy. But it is one I am very happy that I made. My chances of developing breast cancer have dropped from 87 percent to under 5 percent. I can tell my children that they don’t need to fear they will lose me to breast cancer.

It is reassuring that they see nothing that makes them uncomfortable. They can see my small scars and that’s it. Everything else is just Mommy, the same as she always was. And they know that I love them and will do anything to be with them as long as I can. On a personal note, I do not feel any less of a woman. I feel empowered that I made a strong choice that in no way diminishes my femininity.

I am fortunate to have a partner, Brad Pitt, who is so loving and supportive. So to anyone who has a wife or girlfriend going through this, know that you are a very important part of the transition. Brad was at the Pink Lotus Breast Center, where I was treated, for every minute of the surgeries. We managed to find moments to laugh together. We knew this was the right thing to do for our family and that it would bring us closer. And it has.

For any woman reading this, I hope it helps you to know you have options. I want to encourage every woman, especially if you have a family history of breast or ovarian cancer, to seek out the information and medical experts who can help you through this aspect of your life, and to make your own informed choices.

I acknowledge that there are many wonderful holistic doctors working on alternatives to surgery. My own regimen will be posted in due course on the Web site of the Pink Lotus Breast Center. I hope that this will be helpful to other women.

Breast cancer alone kills some 458,000 people each year, according to the World Health Organization, mainly in low- and middle-income countries. It has got to be a priority to ensure that more women can access gene testing and lifesaving preventive treatment, whatever their means and background, wherever they live. The cost of testing for BRCA1 and BRCA2, at more than $3,000 in the United States, remains an obstacle for many women.

I choose not to keep my story private because there are many women who do not know that they might be living under the shadow of cancer. It is my hope that they, too, will be able to get gene tested, and that if they have a high risk they, too, will know that they have strong options.

Life comes with many challenges. The ones that should not scare us are the ones we can take on and take control of.

译文

我的母亲56岁那年因癌症去世，在此之前，她与病魔斗争了将近十年。她一直坚持到看到我最大的孩子出生，还曾拥他们入怀。然而，年龄更小的孩子们却从未有机会认识自己的外婆，感受她的慈爱和蔼。

我们经常说起“妈妈的妈妈”，我试着向孩子们解释这种夺走了外婆的疾病。他们曾经问道，是否同样的事情也会发生在我的身上；我一直告诉他们不用担心。然而事实上，我是BRCA1基因携带者，这种基因存在着缺陷，会导致罹患乳腺癌和卵巢癌的风险大幅提高。

尽管不同女性存在着个体差异，但据医生估计，我患乳腺癌的几率高达87%，患卵巢癌的几率也达到50%。

只有很少一部分乳腺癌病例是由遗传性的基因突变引起的。对于BRCA1基因缺陷携带者来说，平均有65%的几率患上乳腺癌。

当我了解到这一现实，我决定先发制人，尽可能地降低患癌风险。因此，我决定接受预防性双乳切除术。我首先选择乳房手术，是因为我罹患乳腺癌的几率高于卵巢癌，乳房手术也更为复杂。

整个手术治疗过程为期三个月，已于4月27日全部完成。在此期间，我成功地封锁了消息，并继续完成自己的工作。而如今，我把这一切写下来，是希望我的经历能够对其他女性有所助益。听到“癌症”这个词，人们心中依然会生出恐惧与深深的无力感。但是现在，已经有方法通过血液检测获知乳腺癌和卵巢癌的患病风险，进而采取应对措施。

我的治疗是从2月2日开始的。最开始做了一个“乳头保留术”，即排除乳头后方导管的患病可能，同时抽离流经该区域的多余血液。这个过程有些疼痛，会产生大量挫伤，不过有助于成功保留乳头。

两周之后，进行了最主要的手术，切除了乳腺组织，替代以临时填充物。这台手术会持续8小时。你醒来的时候会发现胸部插着引流管和扩张器，感觉就像是科幻电影中的场景。不过术后几天，就能恢复正常生活了。

九个星期之后，进行乳房重塑手术，在胸部植入填充物。至此，治疗全部完成。

这项技术在近年来有了很大的进步，重塑后的乳房会很漂亮。

我写这些是想告诉其他的女性，做出接受乳房切除手术这一决定并非易事。然而，我很高兴自己做出了这样的决定。现在，我的乳腺癌发病率已经从87%降至5%以下。我可以告诉孩子们不用再担心因乳腺癌而失去他们的母亲了。

让我欣慰的是，孩子们对此接受良好。他们可以看见我身上多了一些小伤疤；除此之外，他们的妈妈一如既往，没有任何变化。他们也从中了解到，我爱他们，愿意付出一切换来长久陪伴他们的机会。而就我个人而言，双乳切除术并没有削弱我的女人味。我坚强地做出了选择，而结果不会让我的女性魅力有分毫减弱，这让我充满了力量。

我很幸运，我的伴侣布拉德·皮特在此期间给予我无尽的爱与支持。因此，我想对那些妻子或女友有过这样经历的男士们说：请记住，在她人生的转折点，你扮演着极其重要的角色。我在粉色莲花乳房健康中心接受治疗期间，布拉德始终伴随左右。我们同甘共苦，苦中作乐。我们深知这个抉择对我们的家庭有益，也会让我们更加亲密。事实证明的确如此。

我希望所有读到这篇文章的女性都能够明白，你有权做出选择。我想鼓励所有的女性，特别是那些有乳腺癌或卵巢癌家族病史的女性，去积极搜集信息，寻找能够帮助你渡过这个难关的医学专家，在充分知情的前提下，做出自己的选择。

在我治疗期间，有很多优秀的整体治疗专业医师为我制定了多种手术方案，在此表示感谢。我本人的详细疗程将在适当的时候公布在粉色莲花乳房健康中心的网站上。我希望这种做法能够对其他女性有所帮助。

据世界卫生组织统计，仅仅乳腺癌一种疾病每年就会夺走45.8万人的生命，患病者主要来自中低等收入国家。当前第一要务应该是确保更多的女性有机会接受基因检查和预防性治疗以保障生命，无论她们贫穷富有，有何背景，来自何处。然而，在美国，检测BRCA1和BRCA2基因的费用超过3000美元，这是很多女性所面临的障碍。

我选择公开自己的这段经历，是因为有很多女性并不知道，她们也许生活在癌症的阴影之中。我希望，她们也能够接受基因检查；如果患癌几率较高，她们也能够获知，她们拥有可靠的选择。

人生总是伴随着许多挑战。如果我们有能力承受和掌控，就无需惧怕。

——安吉丽娜·朱莉

滚动招新，主要有颗热爱医学英语的心

7个医学生在用心做的公众号——「Figure1医学」