logo
head-banner

【2016中国HPV论坛专访】Tom Broker教授:宫颈癌筛查的最佳策略及未来发展趋势

2018-01-23 14:23 来源: 中国妇产科网 作者: 中国妇产科网 浏览量: 2889

  中国妇产科网(China-OBGYN)在《2016中国 HPV 论坛》期间就HPV的相关问题有幸采访到了Tom Broker教授(国际HPV学会主席;阿拉巴马大学伯明翰分校(UAB)的生物化学系综合癌症中心病毒学项目共同负责人,并被任命为ADIS研究中心、口腔癌症研究中心和囊性纤维化中心的资深科学家;美国冷泉港实验室电子显微镜实验室的科长兼长期聘用的资深科学家),现将采访内容整理与大家分享。

  国际乳头瘤病毒学会前主席Tom Broker教授专访视频:

  中国妇产科网:Tom Broker先生,请问美国普遍采用的宫颈癌筛查策略是怎样的?(请您从以HPV检测作为初筛,以细胞学作为初筛和二者联合筛查三者的优缺点)分析一下适合中国的宫颈癌筛查策略?什么样的HPV筛查方法更适合中国?

  Tom Broker教授:美国已制定两个不同的同时进行的计划,巴氏细胞学检查和分子筛查。从历史上看,在过去的65年中,巴氏涂片细胞学检查已经把宫颈癌的发病率降低了80%,这是相当成功的。然而在过去的15到20年间已经证明,分子筛选技术更经济实惠,特异性,敏感性和预测性更好。所以,现在的筛查趋势是从细胞学转变为分子探针技术。

  出于经济方面的考虑,开展细胞学检查的从业人员很多,这部分人需要逐渐被更熟悉分子检测技术的人所取代,这是个逐渐过渡的过程。这个过程不仅仅发生在医院等工作场所,同时也发生在大学等教育层面。新一代的医疗技术者对分子生物学更为熟悉。

  直接过渡到分子探针技术将是最有帮助的。在没有细胞学家和其他病理学家的工作队伍,最佳的办法是快速对新一代技术员进行分子生物学理论和技术的培训,包括DNA,RNA,核酸,PCR等技术,DNA杂交和RNA杂交,电子仪器的使用等。结合我自身的经历,开始我是显微镜专家,但同时我也逐渐成为了具有DNA、RNA、杂交领域专业知识的分子生物学家。我发现两个专业各有价值,可以互补,但最终分子生物学通常是最精确的。

  中国妇产科网:HPV定量检测和HPV分型检测这两种检测方法,从检测结果的科学性,与宫颈癌疾病相关性等角度出发,您觉得对预防宫颈癌有着怎样的作用?

  Tom Broker教授:主要目标是要真正了解HPV感染和疾病的自然史。要做到这一点,必须先了解HPV基因型,这应该放在最优先级。原因有多个方面。

  第一,不同的HPV类型感染身体的不同部位。有些感染外部皮肤,有些感染口腔,有些感染生殖道等。前人研究了数十年,才确定哪些HPV类型有特异性,感染身体的不同部位,和不同类型的上皮细胞。我们把这个特征称为病毒的向性。人乳头瘤病毒目前已经超过205种,它们是在感染身体不同部位,在疾病的不同阶段中被发现的。通过区分越来越多的HPV型别,我们对疾病本身研究得更透彻。我们实验室在1980年刚开始研究的时候,只有6个已知HPV型别。到1983年达到18个。而到1985年或1986年已增加到40多个。随着检测技术的改进,这个数字每年都在持续增加。因此,重要的是要具有开放的心态。

  第二,有必要了解哪些病毒型别与癌症的进展联系密切。我们学会了把HPV病毒按低风险和高风险划分。低风险HPV型别,可导致原发性感染或病变,但它会自行消解,有的会继续在体内保留,但不会造成危险病变。相比之下,高风险HPV型别则可能引发癌症的进程。所以,我们必须知道有哪些HPV型别,以确定它们是否是低风险型别,高一点的风险型别,或非常高风险型别。所以HPV分型是绝对至关重要的。

  另外,你的问题还涉及到定量,或者说是病毒拷贝数的检测,DNA或RNA的量。这么多年来我们研究发现,在DNA检测层面,病毒载量,或者说病毒拷贝数,在对癌症的评估来说不太重要。但致癌基因的mRNA表达的量,则非常重要。所以,RNA的转录和基因表达水平的定量更为重要,而病毒DNA拷贝数的定量则不太重要。具体的例子是,我们实验室意外发现,在与HPV相关的癌症中,只有一个单基因组拷贝具有转录活性,而其他所有的基因组拷贝在基因表达水平受到表观遗传学上的沉没抑制。所以,病毒DNA的定量并不重要,因为即使你有500个病毒基因拷贝,但只有一个拷贝得到了表达。这个发现彻底改变了DNA拷贝数是否重要的范例。结论就是,它并不重要。

  中国妇产科网:Tom Broker先生,大量的流行病调查证实HPV16/18是导致宫颈癌的最主要的两个型别, 是否除HPV16//18外需要做具体的型别区分?

  Tom Broker教授:在癌症前期或癌症期,确定在病变位置上存在哪些HPV类型,这是绝对必要的。原因有多个方面。癌症中最常见的病毒确实是HPV 16和HPV 18,这个结论已获得了大量实验结果支持。但是,如果观察病人早20或30年的感染情况,HPV 16型和18型感染并不常见,其他类型比较常见。所以从良性感染或低度病变发展为癌症的过程中体现了对HPV 16和HPV 18型的选择倾向。尽管如此,高达30%的子宫颈癌的是由其他类型引起的。因此不能局限观察HPV 16和18型,否则会导致遗漏30%的(子宫颈癌)案例,此数量全球每年约100000名妇女。基因分型不可忽视的两点,主要与病情发展阶段有关。如果是做早期筛查,主要可以确定16型或18型感染的妇女,或确定其他的14或16种易致癌HPV病毒亚型,便于跟踪感染情况。显然感染HPV 16和18型的妇女存在着致癌高风险。但是,其余30%的可能致癌感染也不能忽略。另一个重要原因是多重感染是非常常见的。妇女可能不是单一HPV类型感染,她可能有2,3个或多重的(HPV类型)感染。在我对女性HIV艾滋病者的研究中,他们的免疫系统薄弱。其中有些患者在生殖道粘膜有11种不同的HPV亚型,她病得非常严重。我们发现,在同一时间伴随2,3,4,或5种类型的感染预示着癌症发展的更大风险。其他病毒类型似乎增补了HPV 16和18的活性。因此多重感染的妇女有更高的患癌风险。

  中国妇产科网:Tom Broker先生,请问您对宫颈癌筛查自取样方法怎么看?他的发展趋势将如何?

  Tom Broker教授:自筛查是降低HPV患病风险的公共健康方法中的一个重要组成元素。女人要么不愿去妇科医生或接受家庭医生的检查,有些甚至没有进行检查的医疗资源。在家里检查可以保护隐私,也为每位妇女提供接受筛选的机会。有多种方式都可以实现自筛查,且是非常有效,其有效性几乎等同于在医院接受的检查。取样结果可包装送至实验室进行集中评估。可见,自取样是一个非常重要的方面,可以节省时间,也可以更好地保护隐私。而且很多时候,妇女自己通常可以更彻底地在生殖道的不同部分来采集潜在受感染细胞,因此成功率很高,也非常经济的一种方式,并覆盖了更广的检查范围。也因为在这些实验室有邮寄及实验室的记录,更便于数据管理,这对整个HPV的研究极具意义。

  中国妇产科网:请问您对宫颈癌疫苗的看法?它是不是未来宫颈癌的解决方案?

  Tom Broker教授:我认为疫苗是预防的重要组成部分,但不足以使整个社会根除HPV或者形成保障。在我看来,有一个5步策略可以预防和控制HPV疾病。预防性疫苗显然是一个组成部分。(但是)现阶段,疫苗价格太贵,在社会也引起广泛争议。虽然疫苗是安全的,有效的且绝对能做到预防HPV感染。但遗憾的是很多人并不觉得预防性疫苗是必要的,在大多数国家中总体接受率相当低。其他许多社会和政治力量导致非常高比例的年轻人未接种疫苗。第二个重点,或许相对于上一点更重要,是筛查。有效的国家分子筛查方案在发现早期病变中是绝对必要的。我个人认为,筛查应该开始于一个相对年轻的年龄,从5年内有性行为开始。并且至少能监控是谁感染了HPV,谁可能处于持续感染并可能发展成疾病。第三个方面是仍处于研究和开发阶段的治疗。一旦HPV病变被确定,在理论上(这种确诊)迟早会到来,此时我们需要治疗方案,一种简单,有效,外用治疗使感染消失。第四个重点是,公众教育和医生的教育。这样人们就了解HPV疾病和与之相关的预防措施,控制,管理和治疗。最后一点是公共政策,监管层面,政府层面和媒体公关来倡导医疗服务能力,关于HPV筛查和恰当的治疗护理。HPV疾病的控制不能仅从一方面来进行,而是需要同时进行这五个方面。首先是通过媒体和公众引起关注,但最终是政府监管方面认可的临床试验或建立实施的疫苗和筛查项目,这些方面都变得至关重要。

  现在回答有关男性的这一问题。男性有很大的可能性感染HPV。HPV是一种性别中立的感染源,像女性一样,男性会感染严重的疾病。包括男性和年轻男子的疫苗项目将是一个伟大的公共政策,拥有高性价比,不但可以破坏男女之间(病毒)的循环传播,又因为男人也会感染疾病。所以我认为所有提供给女性的筛查或疫苗接种都应该提供给男性。我还想再阐述一个观点,那就是危险因素。显然,HPV相关的疾病必然涉及到一种或多种HPV类型,但是作为生活的一部分人们一定暴露于其他易感的危险因素。HPV是人类生存环境的一部分。HPV病毒无处不在。考虑到HPV的大量亚型,地球上的每一个人都有某些HPV在他们的身体里,在皮肤中或粘膜中或两者都有,它们不可避免。所以HPV病毒是可以避免的想法是不可能的。HPV无处不在,人们会感染到HPV病毒。第二件事是风险。有充分的证据表明男性或者女性,尤其是女性,过早的性生活是使生殖道感染HPV的高风险行为。延迟发生性生活则有更多的保护作用,保护的程度取决于年龄。非常年轻的女孩,如果她们感染了病毒,不仅原发感染的风险高,发展成癌症的风险也高。在我看来,第二个主要的危险因素是HPV上皮细胞的反复损伤和愈合。我们从实验和自然历史得知HPV感染组织的反复损伤和愈合更可能发展成癌症。第三大的风险因素是个体的免疫状态。而且在生活过程中有很多很事情可以引起免疫功能缺陷。这也许是我最想要强调的内容。我想阐述在人们的生活中各类免疫抑制事件。其中之一是压力,包括情绪紧张,身体压力,营养应激和晒伤。所有这些因素可以激活潜伏的,亚临床的HPV病毒。妊娠是第二个常见的激活HPV病毒的原因。为了不抗拒发育中的胎儿和胚胎,怀孕的妇女是处于免疫调节状态,但同时,她对生殖道HPV持续性的激活更受影响。第三件事是衰老。随着时间的推移我们的免疫系统变得越来越虚弱。其中宫颈癌出现最频繁的年龄是在人们55,60或70岁,因为免疫系统越来越弱。还需过其他重要的原因诸如实体器官移植等。患者植入一个新的肾脏,肝脏,心脏,肺或胰腺等,在经过约10年的免疫抑制,使用免疫抑制药物的人一定会爆发全身疣。另一类是带有自身免疫疾病的患者,如类风湿性关节炎,红斑狼疮和克罗恩病,对于正在服用免疫抑制药物来控制他们的自体免疫疾病的患者,潜伏的HPV会被激活。当然HIV艾滋病是免疫被抑制的。而另外一个是接受癌症化疗的患者,他们免疫能力枯竭,导致HPV被激活。所以,如果把这些因素都考虑在内,我们的一生不可能不经历一次或多次免疫被抑制。这就是为什么HPV已成为很大的医学问题。每个人都可能携带。每个人都可能在生活中的某一时刻会表达它。

  中国妇产科网:Tom Broker先生,中国HPV数据库项目自2011年启动,可否请您谈一下您个人对这个项目意义的看法?

  Tom Broker教授:HPV数据库是必不可少的。尽管自70年代中期起,在世界范围内就进行了关于HPV的深入研究,我们仍在不断学习有关感染的自然发展史,风险,以及可能结果。至关重要的是HPV的基因分型,多重感染,及其他风险因素,这些可能增加或降低他们的感染风险。(HPV)数据库,其中发展成为癌症的患者的记录,是能帮助我们了解感染史细节的唯一途径。整个生物医学界都能对数据库做出贡献,且更应该支持。

China Obstetrics and Gynecology Network (China-OBGYN) Interview with Professor Tom Broker (Former President of the International Papillomavirus Society, Professor of Biochemistry and Molecular Genetics, University of Alabama) during The China Academy HPV Forum 2016

Chengdu

5/14/2016

Transcripts of Professor Tom Broker

1. The United States has 2 different parallel plans in place. Historically it has been pap smear cytology for the last 65 years, which has been a reasonably successful program in reducing cervical cancer incidence by about 80% compared to before the pap smear screening. However for the last 15 to 20 years, molecular based screening technologies have proven that they are far more affordable, specific, sensitive and predictive. So the trend now is to convert from cytology to molecular probe technologies. The preferable approach (would be):

Sensitive

Specific

Predictable

One of the economic challenges is that you have a large number of people who do cytology, who collect pap smears and interpret pap smears. That is a large number of people. And they have to be displaced, to be replaced by people with greater familiarity with molecular technology, so basically the transition of the work force from cytology to molecular screening capabilities. That occurs not only in the work place, but at the universities - the educational level. The new generation of medical technologist is much more familiar with molecular biology.

The immediate transition to molecular probe technologies would be most helpful. When there is not an established work force of cytologists and other pathologists, who are established in their methodology, the optimal approach would be to quickly train the new generation of people with skills in understanding of DNA, RNA, nucleic acids, technologies like PCR, and DNA and RNA hybridization, and the use of electronic instrumentation, as compared to the specialists who are experts in microscopy. I will simply say at a personal level, I began as a microscopist, but in parallel became a molecular biologist with expertise in DNA and RNA structure and hybridization. I found that each had their value in a complementary way, but ultimately the molecular biology is usually the most definitive.

2. The primary objective at this point is to truly understand the natural history of HPV infection and diseases. To do so, it is absolutely essential to understand the HPV genotypes. That would the highest priority. The reason is multiple folds. One is that the different HPV types infect different parts of the body. Some are in the external skin, some are in the oral cavity, genital tracks and so forth. It took decades of research to determine what HPV types were specific to different parts of the body and the different types of epithelia.

We call that the tropisms of the virus. An important point is that human papillomaviruses now numbered more than 205 kinds. They were determined by isolating whatever HPV was associated with different parts of the body and different stages of disease. So the way we could have known that is by gradually identifying more and more of the types. When we started out in 1980, my laboratory, there were only 6 known types. By 1983, there were 18 known types. But by 1985 or 1986, they were more than 40 known types, and it has continued to grow each year with the improved technology, and having an open mind to what is important. The other thing I want to say on this subject is the necessity to understand which of the viruses are associated with diseases that progress towards cancer. We have learnt to divide or categorize the HPV types according to low risk and high risk. The low risk can cause primary infection and lesion, but it will spontaneously resolve or it will be maintained, but it will not be ultimately kill. In contrast, the high risk oncogenic viruses really have a possibility progressing towards cancer. Again, you had to know which HPV types were present to determine if they were of the low risk types, or the higher risk (types), or the very high risk types. So typing was absolutely crucial.

The additional part of your question was with respect to quantification, or measurement of copy number, or the amount of DNA or RNA. We found over the years that the copy number, or the viral load was less important in the cancer evaluation at the level of DNA. But that was very important was the amount of messenger RNA from oncogenes, the cancer-causing genes. So quantification mattered more at the level of RNA transcription and gene expression. But DNA copy number mattered less. Quite specifically our lab discovered, unexpectedly, that in a cancer associated with HPV, that only a single genomic copy of the HPV was transcriptionally active. Every other copy was silenced using epigenetic suppression of gene expression. And so it did not matter if you had 500 copies, because only was been expressed. That completely changed the paradigm of whether DNA copy number matters. It does not.   

3. It is absolutely essential to identify which HPV types might be present in any lesion, of pre-cancer or an invasive cancer. The reason is multiple folds. The most common viruses found in cancers that have already been developed indeed are HPV 16 and HPV 18. But if you look in early stage infections, 20 or 30 years earlier in that person’s life time, type 16 and 18 are not very common at all. Other types are. So the risk of progression from benign infection and low grade lesion towards cancer has a selection process towards HPV 16 and 18. Having said that, about 30% of cervical cancers are caused by other types that are also high risk. You cannot limit yourself to look in HPV 16 and 18. You are going to miss 30% of the (cervical cancer) cases, which (are) approximately 100000 women globally each year. There is two points for the genotyping, and it largely depends on the stage. If you are doing early screening, you want to identify those women who have type 16 or 18, or the other fourteen or sixteen viruses that are likely to cause cancer. So that you can follow them. Clearly the women with HPV 16 and 18 are going to be at high risk. But you cannot leave the other 30% behind. But the other important reason is that multiple infections are very common. A woman does not just have a single HPV type. She might have 2 or 3 (types). In my own research looking at women with HIV AIDS, who have a very weak immune system. I found one woman who had 11 different HPV types in the genital mucosa. She was very very sick. We found that co-infections with 2, 3, 4, or 5 types at the same time is a greater predictor of progression towards cancer. The other virus types seem to complement or supplement HPV 16 and 18 activities. So the multiply infected women were at much greater risk of abnormal pap smears and progression towards cancer.

4. Self-screening is a very important component of a public health approach to reducing HPV disease for a great variety of reasons. Women either are reluctant to go to a gynecologist or other family practitioner for annual evaluation, or she may not even have access to such a clinic. On the other hand, in the privacy of your own home, self-collection offers every woman the opportunity to be screened and tested. There are a variety of ways in which the collections can be made. At this point, they are very effective. Essentially as good as what would be carried out in a physician office. They can be packaged up and centrally evaluated in testing labs. Self-collection is an extraordinarily important aspect. It is a time saver. It enables higher level of privacy. And very often the woman would be more thorough in swabbing different parts of the genital tracks to capture potentially infected cells. So the success rate is very high. It is also very economical, and allows for much greater coverage. And also because there is a record of mailing and testing in central lab, there is a better opportunity for data management, which becomes extremely important.

5. I think vaccines are an important component of prevention, but are not sufficient to enable an entire society to eradicate HPV or have protection. In my opinion, there is a 5 fold strategy to preventing and managing HPV disease. Prophylactic vaccines are clearly one component. (But) at this point, they are too expensive, too controversial. A lot of people don’t feel that they are necessary. The overall acceptance rate in most countries is quite low, unfortunately. Because the vaccines are safe, effective, and absolutely do prevent HPV infection. But there are so many other social and political forces at work that a very high fraction of young people are not getting vaccinated. The second essential thing, perhaps even more important is the screening. Effective national molecular screening programs are absolutely essential to identifying early stage disease. In my personal opinion, screening ought to begin at a relatively young age, within 5 years of onset of sexual activity. And at least monitor who is acquiring HPV infection, and who might be at risk of persistent infection that could lead to progressive disease. The third area is still under research and development, and that is therapeutics. Once a HPV lesion is been identified, in the ideal world that will eventually arrive, we need to have treatments – simple, effective, topical treatment - that can make the infection go away. The forth important thing is public education and physician education. So that people are aware of a range of HPV diseases and what can done to prevent, control, manage and treat them. The final thing is public policy that comes from regulatory level, government level, and media relations to advocate for healthcare delivery capabilities, which go back to HPV screening and appropriate therapeutic care. You cannot control HPV with only one of the 5 aspects, you need all 5. And through the media and the general public, but ultimately the government regulatory side of approvals for clinical trials or founding for implementation of vaccines and screening programs all become crucial. One more thing in response to the question about males. Males are very likely to get HPV infections. HPV is a gender neutral infectious agent and men can get serious disease just as women can. Vaccine programs that included boys and young men would be a great public health policy and cost effective both in breaking the cycle of transmission between men and women, but also because men could get the disease. So I think all the pursuit whether it is the screening or vaccination should be available to the males as they are to the females. I would like to also add one other point, (which) is risk factors. Clearly the HPV associated diseases necessarily involve one or more HPV types, but there (are) other susceptibility risks that people are necessarily exposed to as a part of living. HPV is a part of human condition. The viruses are everywhere. They are unavoidable, and considering the wide range of HPV types, every body on earth has some HPV some where in their bodies, cutaneous or mucosa or both. So the idea that some how it is avoidable is impossible. HPV is everywhere and people will get it. The second thing is risk. There is ample evidence that early sexual activity is a high-risk situation for acquiring HPV in the genital track, boys or girls, especially girls. And the delayed onset of sexual activity is more and more protective depending on age. The youngest girls, if they are exposed, have a very high risk of not only primary infection but (also) future progression towards cancer. The second major risk factor in my opinion is repeated wounding and healing of the epithelium that harbors the HPV. We know from experiments and from natural history that repeated wounding and healing of a HPV infected tissue is more likely to progress towards cancer. And the third great risk factor is the immune status of the individual. And there are many many things that can cause immune insufficiency in the course of life. This is maybe my most important statement. I want to elaborate on the types of immunosuppressive events in human life. One of them is simply stress - emotional stress, physical stress, nutritional stress, and sunburn - all can activate HPV that is latent and sub-clinical. The second one, which it is a very frequent cause of activation, is pregnancy. A woman gets pregnant, she is immuno-modulated so she does not reject the developing fetus, embryonic fetus, but at the same time she is more susceptible to the activation of the persistent HPV in the genital track. The third thing is aging. All of us have our immune systems getting weaker and weaker with time. One of the periods of greatest emergence of cervical cancer is in people (who are) 55, 60, and 70 years old, because the immune system is getting weaker. But there are other important reasons such as solid organ transplantation. People who receive a new kidney or a liver or a heart or a lung or a pancreas and so forth who are on immunosuppressive drugs invariably will break out with whole body warts after about 10 years of immunosuppression. Another is people (with) auto-immune diseases, rheumatoid arthritis, lupus erythematosus, Crohn's disease, who are taking immunosuppressive drugs to control their auto-immune disease, will activate latent HPV. And of course HIV AIDS is immunosuppressive. And yet another one is people undergoing chemotherapy for cancer who have a depletion of their immune capabilities and their HPV will activate. So if you add it all together, it is impossible to go through life without experiencing an immunosuppressive event, or many times in the course of life. That is why HPV has become such a big medical problem. Every one is likely to carry it. Every one is likely to express it at some point in life.

6. Databases on HPV disease are essential. Even though HPV has been studied around the world rather intensively since the mid 1970s, we are still continuing to learn about the natural history of the infections, the risks, and the possible outcomes. Crucial to that is HPV genotyping and evaluation of multiple co-infections, as well as the other risk factors that individuals might be presenting them, increased or decreased their susceptibility to infection. The only way we could understand the detail of natural history is through databases, tumor registries that evaluate people who have progressed towards cancer. That is part of the learning process that the biomedical community can contribute and certainly should be supportive.