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大肠癌诊断的局限性

时间:2016-01-28 08:42来源:www.ukthesis.org 作者:英国论文网 点击联系客服: 客服:Damien
大肠癌诊断的局限性

结肠癌是癌症死亡的第二大原因。大多数的病例是零星的,但一些继承家族综合征约占直肠癌(CRC)的5%。 最常见的症状是家族性腺瘤性息肉(FAP)和遗传性非息肉性结肠癌(HNPCC),又称Lynch综合征。这些构成了家族性综合征的3%。其他症状包括Peutz-Jeghers综合征和幼年性息肉病综合征。本文将重点介绍最常见的遗传性结直肠癌。
所涉及的FAP和HNPCC的基因已被确定。 因此基因检测可以提供在这些症状为载体状态屏幕。 识别个人CRC的倾向是重要的,能够在肿瘤早期为他们提供足够的筛查检测机会。

FAP
 
FAP是显性遗传,通过家族谱系呈现具有高度渗透的垂直传播。其经典的表型,包括腺瘤性息肉在结肠黏膜上生长。如果不切除息肉,100%会得结肠癌。息肉发展和结肠恶性肿瘤的平均年龄为16岁和39岁。 我们发现在每 1~70000个出生的美国人会有一个患FAP,占不到1%(戴维森,2007)。FAP是一种单基因遗传病,是由APC基因的突变或缺失引起的(APC)基因是5号染色体上发现的。”95%的APC基因突变导致FAP是无稽之谈(28%)或转移删除(67%) ”(Burt和Neklason,2005)。 剩下的5%是由大型删除或重组引起的。 APC基因是一个肿瘤抑制基因和APC蛋白是Wnt信号通路的组成部分,参与细胞生长的控制”(Burt和neklason,2005)。APC基因的突变导致Wnt信号通路的活化和细胞生长失控。
 
The limitations in Diagnosing Colorectal Cancer
 
Colon cancer is the second leading cause of cancer death. Most of the cases are sporadic but several inherited familial syndromes account for around 5% of all colorectal cancers (CRC). The most common of these syndromes are familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) which is also known as Lynch syndrome. These make up 3% of the familial syndromes. Other syndromes include Peutz-Jeghers syndrome and Juvenile polyposis syndrome. This essay will focus on the most common hereditary CRC's. 
 
The genes that are involved in FAP and HNPCC have been identified. Therefore genetic testing can be offered to screen for carrier status in these syndromes. Identification of individuals who have a predisposition to CRC is important to be able to offer them adequate screening to detect tumours at an early stage.

FAP
 
FAP is dominantly inherited and is highly penetrative showing a vertical transmission through a family pedigree. Its classical phenotype involves the growth of hundreds of adenomatous polyps along the colonic mucosa. If the polyps are not removed there is near a 100% chance of colon cancer. The average age of polyp development and colon malignancy is 16 and 39 years respectively. 'FAP is found in ~1 per 7-10,000 births in the United States population and accounts for less than 1% of all CRC' (Davidson, 2007). FAP is a monogenetic disease and is caused by the mutation or deletion of the adenomatous polyposis coli (APC) gene which is found on chromosome 5. '95% of APC mutations that lead to FAP is either nonsense (28%) or truncating frameshift (67%)' (Burt and Neklason, 2005). The remaining 5% is caused by large deletions or rearrangements. 'The APC gene is a tumour-suppressor gene and the APC protein is part of the Wnt-signalling pathway, involved in cell growth control' (Burt and Neklason, 2005). Mutations in the APC gene therefore cause activation of the Wnt-signalling pathway and uncontrolled cell growth. 
 
There is another variant of FAP known as Attenuated form of FAP (AFAP), it has a later age on onset (>40), less adenomatous polyps (<50) and a lower risk of CRC. Some of these patients will have a mutation in the extreme of the 3' or 5' end of the APC gene compared to those who have extreme polyposis where mutations tend to be in the mid-portion of exon 15. It is important to be able to distinguish between the types of FAP to know where to screen for mutations and how to treat the condition. 
 
It is also important to consider a patient's nationality when they present to clinic. This can determine their inheritance risk and help to locate the mutation. For example Ashkanazi Jews have a high prevalence of the I1307K mutation resulting in a lifetime risk of CRC between 10-20%.
 
诊断-Diagnosis 
 
Genetic testing is important in families who are at risk of FAP due the dominant and high penetrance phenotype. As there is a classical phenotype, FAP is easier to diagnose in clinic. In FAP nearly all mutations consist of truncations of the APC protein. This occurs by point mutations, causing either a frameshift by an insertion or deletion, or a nonsense codon. Genetic Testing for FAP is done by indicating the presence of a disease causing mutation by a Protein Truncation Test (PTT). Then the location of the mutation on the APC gene is found by Conformation-Specific Gel Electrophoresis (CSGE), Single-Strand Conformation Polymorphism (SSCP) or Denaturing Gradient Gel Electrophoresis (DGGE). Once the location of the mutation is localised the APC gene is sequenced to identify the disease-causing mutation. For those large deletions and rearrangements, Southern Blotting, Array CGH and MLPA can be used for identification. If all of these methods fail to identify the mutation, linkage testing to the APC gene can be done. As it has become cheaper to sequence the APC gene recently many clinics skip the process of locating the area of mutation and sequence the whole gene.
 
影响-Implications 
 
The APC gene is large and the mutations spread along it. This can make it difficult to locate the mutation. As many families have unique mutations it may be difficult to decide if the mutation found is actually pathogenic. In fact in patients presenting with phenotypical classical FAP, known pathogenic mutations are only found in 85% of them. The rest, although they may have changes in the APC gene it is unknown what these changes mean. As this information is uninformative it is not possible to give patients a risk of getting CRC or to screen their families to be able to exclude those who are not at risk. 
 
All of the molecular tests used for FAP have their advantages and disadvantages. PTT fails to detect truncations that occur at the very end or beginning of a gene and large mutations. Additionally it cannot detect missense mutations. However, if it does find a mutation it is always disease causing. CSGE does detect more than 90% of mutations present. SSCP detects between 60%-95% of mutations and DGGE can detect up to 90% of sequence changes. Array CGH will miss small deletions and MLPA cannot detect balanced translocations and is sensitive to impurities. Therefore some mutations are being missed. (责任编辑:anne)


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