单核苷酸多态性与结直肠癌关系研究进展

结直肠癌是一种多因素共同作用的疾病,对结直肠癌的研究应该从多基因水平考虑,单核苷酸多态性作为一种新的研究肿瘤基因改变的方法,在结直肠癌的研究中有重要作用.寻找结直肠癌特异性单核苷酸多态性,对筛选高危人群,预估发病风险,具有重要意义.     

结直肠癌组织中激肽释放酶10基因的表达及其与临床及病理的关系

目的 探讨激肽释放酶10（KLK 10）基因在结直肠癌组织中的表达及其与结直肠癌临床及病理特征的关系。方法 采用荧光实时定量PCR技术,检测KLK 10 mRNA在63例结直肠癌患者癌及相应正常结直肠组织中的表达;采用免疫组织化学及免疫蛋白印迹法（western blot）定位及检测其蛋白表达。对16例结直肠癌及相应正常结直肠组织基因组DNA KLK 10基因的6个外显子进行直接测序,分析其单核苷酸多态性（SNP）。结果 97％（61／63）患者的结直肠癌组织中可检测到KLK 10mRNA表达,结直肠癌组织中KLK 10基因的表达量显著高于相应正常结直肠组织。KLK 10基因于结直肠组织中的表达与淋巴结转移及临床分期显著相关（P〈0．05）。79％（50／63）患者的结直肠癌组织中可检测到相对分子质量为30000的蛋白表达。结直肠癌组织中KLK 10基因外显子3第50密码子有丙胺酸（GCC）-丝氨酸（TCC）改变,其中25％（4／16）为野生型GCC,56％（9／16）为杂合型GCC／TCC,19％（3／16）为纯合型TCC。结直肠癌及相应正常结直肠组织中,KLK 10基因外显子4有4个密码子,即106[甘氨酸（GGC）-甘氨酸（GGA）]、112[苏氨酸（ACG）-苏氨酸（ACC）]、141[亮氨酸（CTA）-亮氨酸（CTG）]及149[脯氨酸（CCG）-亮氨酸（CTG）]为SNP;相应正常结直肠组织中未发现有体突变。结论 KLK 10基因在结直肠癌组织中为异常高表达,且与癌淋巴结转移与临床分期显著相关,是结直肠癌潜在的预后标记物。     

Transmission of breast cancer polygenic risk based on single nucleotide polymorphisms

AimThe goal of the present study was to further refine how polygenic risk scores may be used in a large population and to quantify the transmission of risk score through generations.MethodsAllele frequencies from the 1000 Genomes data for 159 single nucleotide polymorphisms associated with breast cancer risk were used. A breast cancer risk score was calculated among 100,000 people. Choosing two “parents” and the alleles they transmit at random, 100,000 “daughters” were simulated. The population was divided by deciles of risk score. Comparing mean risk score in the mother and daughter populations provided information regarding the general relationship at a population level. By examining the distribution of daughter's risk score within each decile of maternal risk score, the transmission was evaluated at the subject level.ResultsMean values of risk score were 85.1 (St Dev = 7.5) and 85.0 (St Dev = 7.5) for the populations of mothers and daughters, respectively (mean absolute difference = 0.02, p = 0.48). When examining the transmission of risk score from mothers to daughters in specific deciles of risk, statistically significant differences were observed in all deciles (ranged between 0.001 and < 2.2 × 10⁻¹⁶).ConclusionThe relationship at the subject level will not provide information regarding prevention and screening of offspring based on the knowledge of parents' risk score alone. The present results show that risk estimation by polygenic risk scores is personal, and evaluation of risk score is required for each individual.     

测序法研究XRCC1基因单核苷酸多态性与结直肠癌遗传易感性的相关性

目的探讨x线交叉互补基因1（XRCCl）单核苷酸多态性（SNP）与结直肠癌遗传易感性的相关性。方法采用SNaPshotSNP分型技术方法,对136例结直肠癌病例（病例组）和214例成组匹配的正常体检者（对照组）外周血中的XRCCl基因的rs25487、rs25489和rs1799782等3个SNP位点进行分型,针对每个位点分析共显性、显性、隐性、超显性和叠加作用5种不同的遗传模型。分析XRCCl不同基因型与结直肠癌发生风险的相关性。结果XRCCl基因3个SNP位点25487G／A、25489C／T及1799782C／T变异等位基因在病例组的频率分别为0．20、0．11和0．32。对照组分别为0．23、0．13和0．34。单倍型分析显示。GCT、GCC、ACC和GTC为最常见的4种单倍型,其OR值分别为1、1．35、0．90和0．84,病例组与对照组单倍型的分布差异无统计学意义（P〉0．05）。单位点分析结果显示,在5种不同的遗传模型中,3个SNP位点的基因型均与结直肠癌发生风险无相关性（P〉0．05）。结论XRCCl基因的3个SNP位点（rs25487、rs25489、rsl799782）均与结直肠癌的发生无明显相关性。     

Systematic search for single nucleotide polymorphisms in the resistin gene: the absence of evidence for the association of three identified single nucleotide polymorphisms with Japanese type 2 diabetes

Resistin is a novel polypeptide specifically secreted from adipocytes, and its serum levels are increased in obese diabetic mice. Resistin antagonizes insulin and could account for insulin resistance. To determine whether there are single nucleotide polymorphisms (SNPs) in the resistin gene associated with type 2 diabetes, sequences for 24 Japanese type 2 diabetic patients were initially analyzed using PCR direct sequencing. Three SNPs were found in the introns, but none were present in the coding regions. The allele frequencies of genomic -167C>T, +157C>T, and +299G>A in 99 Japanese control subjects were determined to be 3.5, 6.6, and 39.4%, respectively. In each pair of these SNPs, linkage disequilibria were found between either -167C>T and +299G>A or +157C>T and +299G>A. A linkage disequilibrium was also detected among -167C>T, +157C>T, and +299G>A, and only four of the eight possible haplotypes defined by these SNPs were found. A comparison of the frequencies of these SNPs and haplotypes between 99 type 2 diabetes and 99 control subjects revealed no evidence for any association. These identified SNPs, which were in linkage disequilibrium, represent potentially useful tools for searching for their association with specific phenotypes of diabetes.     

Validation of single nucleotide polymorphisms associated with acute rejection in kidney transplant recipients using a large multi-center cohort

There have been numerous reports proposing a statistically significant association between a genetic variant, usually in the form of a single nucleotide polymorphism (SNP), and acute rejection (AR). Unfortunately, there are additional publications reporting a lack of association with AR when a different cohort of recipients was analyzed for the same SNP. The objective of this report was to attempt replication of these published finding in our own kidney allograft recipient cohort. We analyzed 23 genetic variants, previously reported to have a significant association with AR, using a cohort of 969 clinically well-defined kidney transplant recipients. Only one SNP, rs6025 (Leiden mutation), within the coagulation factor V gene, showed a significant association with a P-value of 0.011 in a race-adjusted analysis and a P-value of 0.0003 in multiple variable analysis. An additional SNP, rs11706052 in IMPDH2, gave a modest P-value of 0.044 using multiple variable analysis, which is not significant when multiple testing is taken into consideration. Our results suggest that careful validation of previously reported associations with AR is necessary, and different strategies other than candidate gene studies can help to identify causative genetic variants associated with AR.     

单核苷酸多态性与前列腺癌的研究进展

前列腺癌是影响西方国家男性健康的常见恶性肿瘤,而单核苷酸多态性(SNPs)作为第3代遗传标记可以影响到前列腺癌的发生、发展及预后。相同SNPs在不同种族间和前列腺癌的关系可能存在差异;本文就与前列腺癌相关的基因进行分类,描述不同SNPs与前列腺癌的关系。SNPs可以预测前列腺癌治疗过程中可能的不良反应,同时也可预测前列腺癌的患病风险,但目前仍存在一定的局限。     

Single nucleotide polymorphisms associated with nonsyndromic cryptorchidism in Mexican patients

Cryptorchidism is a frequent genitourinary malformation considered as an important risk factor for infertility and testicular malignancy. The aetiology of cryptorchidism is multifactorial in which certain SNPs, capable of inhibiting the development of the gubernaculum, are implicated. We analysed 16 SNPs by allelic discrimination and automated sequencing in 85 patients and 99 healthy people, with the objective to identify the association between these variants and isolated cryptorchidism. In two different patients with unilateral cryptorchidism, we found the variants rs121912556 and p.R105R of INSL3 gene in a heterozygous form associated with cryptorchidism, so we could considered them as risk factors for cryptorchidism. On the other hand, SNPs rs10421916 of INSL3 gene, as well as the variants rs1555633 and rs7325513 in the RXFP2 gene, and rs3779456 variant of the HOXA10 gene were statistically significant, when the patients and controls were compared and could be considered as protective factors since are predominantly present in controls. The genotype–phenotype correlation did not show statistical significance. With these results, we could conclude that these polymorphisms can be considered as important variants in our population and would contribute in the future knowledge of the aetiology and physiopathology of cryptorchidism.     

3号染色体两单核苷酸多态性与中国前列腺癌风险的相关性研究

目的:探讨3号染色体常见单核苷酸多态性(SNP)与中国前列腺癌(PCa)发病风险的关系,并探讨其与临床相关危险因素的关系。方法:采用病例对照设计方法,选取124例PCa患者以及年龄、性别匹配的111例正常对照人群作为研究对象,使用聚合酶链反应-高分辨熔解曲线(PCR-HRM)技术结合测序验证法检测SNPrs10934853和rs2660753基因型与等位基因分布情况,分析两位点危险基因型的累积效应,并探讨其不同基因型与PCa患者临床相关危险因素间是否存在相关性。结果:①rs10934853的基因型AA、CC、AC在PCa组中分别有28例(22.8%)、46例(37.4%)、49例(39.8%),在正常对照组中分别有24例(22.0%)、34例(31.2%)、51例(46.8%);rs2660753的基因型AA、GG、AG在PCa组中分别有13例(11.0%)、59例(50.0%)、46例(39.0%),在正常对照组中分别有9例(8.8%)、47例(45.6%)、47例(45.6%),2个SNP的基因型频率与等位基因频率在2组间的分布均无显著性差异(P值分别为0.520、0.582)。②SNP rs10934853和rs2660753两独立变异危险基因型累积效应分析发现:与野生型组相比较,含有危险基因型的两组PCa的发病风险略有增加(OR值分别为1.831、1.968),但组间差异不具有统计学意义(P>0.05)。③SNP rs10934853和rs2660753的不同基因型与PCa患者不同临床相关危险因素间均无显著相关性(P>0.05)。结论:SNP rs10934853和rs2660753与中国PCa的发生无明显相关性,可能与中国PCa的发病风险无关。     

Hereditary colorectal cancer associated with polyposis syndromes

This study reviews different aspects of hereditary colorectal cancer associated with three polyposis syndromes: familial adenomatous polyposis, juvenile polyposis coli and Peutz-Jeghers syndrome. All these syndromes share some similarities: low incidence, autosomal dominant inheritance, genetic predisposition to colorectal cancer and/or other extracolonic cancers. Classical familial adenomatous polyposis is clinically defined by the presence of hundreds of adenomatous polyps in the colon and rectum, whereas less than 100 polyps are found in attenuated familial adenomatous polyposis. Without prophylactic colectomy, colorectal cancer develops inevitably by the age of 40. Restorative proctocolectomy with ileal anal-pouch anastomosis is the operation of choice in familial adenomatous polyposis. In juvenile polyposis coli, 50-200 hamartomatous polyps are found in the colon, rectum, stomach and small bowel. Life-time cumulative risk for colorectal cancer is estimated to be 50%. Prophylactic colectomy is required only in cases in which endoscopic surveillance is not able to control polyp development. Hereditary mixed polyposis syndrome is a variant form of juvenile polyposis coli, consisting of multiple mixed adenomatous, hyperplastic and hamartomatous polyps. Peutz-Jeghers syndrome is characterized by multiple hamartomatous polyps located in the small bowel, colon and stomach. Small bowel follow through and colonoscopy is advised for surveillance. Surgery is warranted only in cases of polyps larger than 1 cm. The causative genes of these syndromes have been cloned. Molecular genetic testing of affected and at-risk individuals is proposed in order to advise surveillance and management.     

Variation in three single nucleotide polymorphisms in the calpain-10 gene not associated with type 2 diabetes in a large Finnish cohort

Variations in the calpain-10 gene have recently been reported to be associated with type 2 diabetes in a Mexican-American population. We typed three single nucleotide polymorphisms (SNPs) in the calpain-10 gene (SNPs 43, 56, and 63) to test for association between variation at these loci and type 2 diabetes and diabetes-related traits in 1,603 Finnish subjects: two samples of 526 (Finland-U.S. Investigation of NIDDM Genetics [FUSION] 1) and 255 (FUSION 2) index case subjects with type 2 diabetes, 185 and 414 unaffected spouses and offspring of FUSION 1 index case subjects or their affected siblings, and 223 elderly normal glucose-tolerant control subjects. We found no significant differences in allele, genotype, haplotype, or haplogenotype frequencies between index case subjects with diabetes and the elderly and spouse control populations (all P > 0.087). Although variation in these three SNPs was associated with variation in some type 2 diabetes-related traits within each of the case and control groups, no consistent pattern of the implicated variant or combination of variants was discerned. We conclude that variation in these three SNPs in the calpain-10 gene is unlikely to confer susceptibility to type 2 diabetes in this Finnish cohort.     

Acute colonic perforation associated with colorectal cancer

Our purpose was to evaluate long-term outcome in patients presenting with acute colonic perforation in the setting of colorectal cancer. We conducted a retrospective review of 48 consecutive patients presenting with acute colonic perforation associated with colorectal cancer at a single institution. Patients presented either with free air or acute peritonitis. No patients with colonic obstruction were included. Forty-eight patients presented with colon perforation. Thirty-six had perforation at the tumor, 11 proximal to the tumor, and one distal to the primary tumor. Patients who perforated proximal to the tumor were older (74.5 +/- 2 vs 64.7 +/- 3; P < 0.04) and had a longer length of stay (46.8 +/- 17 vs 11.6 +/- 1 P < 0.001). Fourteen patients had stage II disease, 19 stage III, and 15 stage IV. Thirty-day mortality was 14 per cent (n = 7) with nine in-hospital deaths. Of 30-day survivors 29 (60%) had curative resection (21 with local perforation and nine with proximal perforation). Of these 14 received adjuvant chemotherapy. Eleven patients (33%) had either unresectable or metastatic disease on exploration. Mean follow-up was 21.5 months. Ten patients developed metastatic disease after potentially curative resections. Of these nine patients had perforations of the primary tumor. Three patients developed local recurrence and all had local tumor perforations. One-year survival was 55 per cent (n = 16). Five-year disease-free survival was 14 per cent (n = 4). There were no long-term survivors after perforation proximal to the tumor, although disease stage was comparable in both groups. We conclude that perforation proximal to a cancer is associated with a higher perioperative mortality and worse long-term outcome when compared with acute perforations at the site of the tumor. Long-term survival requires both aggressive management of the concomitant sepsis and definitive oncologic surgery.