Lynch综合征研究进展

摘 要：Lynch综合征（Lynch syndrome,LS）又称遗传性非息肉病性结直肠癌,是最常见的一种遗传性结直肠癌综合征,占结直肠癌的２％～５％。指的是那些具有错配修复（MMR）基因突变导致易患结直肠癌和其他恶性肿瘤的个体。文章就国内外近10年关于MMR基因突变的特点和对LS的诊断和筛选及其应用的进展作一综述。     

云南省7个Lynch综合征家系中致癌基因突变研究

目的 探讨云南省7个Lynch综合征（Lynch syndrome,LS）家系中常见致病基因突变情况。方法 选取昆明医科大学第一附属医院肿瘤科2008年3月—2013年12月收治的7个经过免疫组织化学检测和微卫星不稳定检测确定为MSI-H和dMMR的家系先证者,并且这7个家系都符合AmsterdamⅡ诊断标准。采用目标区域捕获结合高深度测序技术,对家系首发患者的遗传性结直肠癌相关5个基因外显子及其邻近±2 bp内含子区变异进行分析。结果 7个家系（2个白族家系、2个彝族家系、3个汉族家系）中,2个白族家系和2个彝族家系均未发现已知突变位点。结论 Lynch综合征家系致病突变可能存在民族差异。     

Lynch 综合征的诊治进展和家系管理*

Lynch 综合征（Lynch syndrome,LS）是遗传性结直肠癌中最常见（约占5%）的一类常染色体显性遗传病,错配修复基因的种系突变和微卫星不稳定是其区别于其他遗传性结直肠癌的两大特点。近年来,研究发现在诊断和治疗上,LS与散发性结直肠癌有一定的区别;此外除了患者本人的诊断和治疗,整个家系的管理也至关重要。此类疾病应当引起临床高度重视。本文对LS的最初定义、诊断标准和筛查标准的变迁、最新治疗进展和家系管理进行综述,旨在帮助临床了解LS,给予患者合理的治疗,以及对其家系成员适当的干预和监控,尽可能降低患癌风险。      

遗传性非息肉病性结直肠癌的研究进展

遗传性非息肉病性结直肠癌（ｈｅｒｅｄｉｔａｒｙｎｏｎ－ｐｏｌｙｐｏｓｉｓｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒ，ＨＮＰＣＣ）是一种常染色体显性遗传性肿瘤，外显率高达８０％～８５％，约占所有大肠癌的５％～１５％。与一般散发性大肠癌相比，它在临床表现、病理学检查和遗传背景上都有着独特的特征，其诊断主要根据临床与家系表征而定。近年来关于ＨＮＰＣＣ的国内外研究范围有新的积累，获得了一些新的认识和看法。１国际诊断标准的确立与修改为了规范和统一ＨＮＰＣＣ的诊断，便于世界范围内的协作研究，１９９０年国际ＩＣＧ－ＨＮ…     

遗传性非息肉病性结直肠癌家系分析

目的　探讨遗传性非息肉病性结直肠癌在我国的发病遗传规律以及流行病学特点。方法　自 1999年 1月至 2 0 0 2年 12月 ,对天津市人民医院 (原名天津市滨江医院 )收治的 2 92例结直肠癌患者进行家系调查 ,从中筛选出符合以下标准的遗传性非息肉病性结直肠癌家系 3 8个 ,对家系的肿瘤发生率、肿瘤谱和临床特点等进行了分析和总结。诊断标准使用Amsterdam标准Ⅰ、Amsterdam标准Ⅱ (ICG HNPCC)和日本HNPCC诊断标准。结果　 3 8个遗传性非息肉病性结直肠癌家系中共有 14 5例癌症患者 ,其中男性 76例 ,女性 69例 ,男女比例为 1.1∶1。原发性结直肠癌平均诊断年龄为 ( 5 5 .73± 15 .88)岁 ,在所有 99例结直肠癌中 ,左半结肠癌及直肠癌 2 9例 ,占 2 9.3 % ;右半结肠癌 70例 ,占 70 .7% ,右半结肠癌占有绝对的优势 ;异时性多发性原发结直肠癌患者占大肠癌患者的 13 .1% ( 13 /99) ;HNPCC相关肿瘤共 46例其发生率由高到低前三位是 :子宫内膜癌 9例 ( 19.6% )、乳腺癌 7例 ( 15 .2 % )、肺癌、胃癌各 6例 ( 13 .0 % ) ;在男女性共患癌中 ,除胰腺癌、纵隔癌外 ,男性发生率均高于女性 ;第一代、第二代以及第三代患者的平均诊断年龄有逐渐年轻化的趋势 ,并具有统计学意义。结论　我国遗传性非息肉病性结直肠癌很可能     

Lynch 综合征相关性子宫内膜癌的研究进展

摘 要：Lynch综合征相关性子宫内膜癌(LS-EC)与散发性子宫内膜癌不同,该病是常染色体显性遗传病,是由于DNA错配修复基因（MLH1、MSH2、MSH6 及PMS2）的突变或异常表达引起的。LS-EC再发肿瘤风险较高,及时诊断及治疗非常重要。近年来发达国家采用免疫组化、微卫星不稳定性和基因检测等相结合的分子诊断方法,大大提高了LS-EC的诊断率。全文针对LS-EC的遗传学改变、临床病理特点、筛查及诊断、预防、治疗进行了综述。     

Lynch综合征研究进展

[摘要] Lynch 综合征（Lynch syndrome,LS）是一种常染色体显性遗传病,是由于几种DNA 错配修复（mismatch repair,MMR）基因（MLH1、MSH2、MSH6、PMS2）中的一种出现种系突变,或由于EPCAM基因缺失导致MSH2 表达丢失引起。LS是遗传性结直肠癌（colorectal cancer,CRC）最常见的原因,其特征为患CRC和子宫内膜癌（endometrial cancer,EC）的风险显著增加,且存在发生其他几种恶性肿瘤的风险。对于LS 的诊断,目前几种临床病理学标准（如阿姆斯特丹标准等）已被用于识别存在Lynch 综合征风险的个体。然而,这些标准的敏感性及特异性有限,仍有赖于临床医生对LS的警惕并关注其家族史。伴有MMR基因变异的LS相关肿瘤通常具有微卫星高度不稳定的特征,由于移码突变新抗原的存在,可以激发强大而持久的免疫反应和肿瘤浸润淋巴细胞浸润,所以对于LS患者,免疫检查点抑制剂将会是一种很有前景的治疗方法。由于LS是一种基因遗传病,与DNA错配修复缺陷具有独特关系,对其的充分理解对相关肿瘤的诊断、预防和治疗具有重要的临床意义。     

遗传性非息肉病性大肠癌的诊治进展

遗传性非息肉病性结直肠癌(HNPCC)是一种常染色体显性遗传病，错配修复基因的种系突变是发病基础，在散发性大肠癌中遴选HNPCC家族，并对HNPCC患者及其家属进行基因检测可以发现HNPCC相关肿瘤的高危人群，使家族中发病率低的成员免受长期医疗随访之苦，而且对HNPCC相关肿瘤患者进行预防性手术有较大的临床意义。     

遗传性非息肉病性结直肠癌研究进展

结直肠癌的发生率呈逐年上升趋势,已成为某些发达国家和地区导致死亡的主要疾病之一.遗传性非息肉性结直肠癌(hereditary non-polyposis colorectal cancer,HNPCC)作为结直肠癌的一种,为常染色体显性遗传,约占结直肠癌的5％-15％,HNPCC又称Lynch综合征,其原因主要是错配修复基因(mismatch repair genes,MMR)缺陷,导致MSI,从而引起结直肠癌,近年来其相关研究已受到普遍关注.     

Recent discoveries in the molecular genetics of Lynch syndrome

Lynch syndrome is the inherited predisposition to cancer caused by a germline mutation in a DNA mismatch repair gene. The consequent tumors have a characteristic microsatellite instability (MSI) phenotype. Genomic sequencing of Lynch syndrome-associated colorectal cancers (CRCs) has demonstrated that these tumors have a substantially greater number of mutations than non-MSI CRCs, and that the target mutations driving tumor behavior are also different from what occurs in sporadic tumors. There are multiple non-Lynch syndrome entities that can create clinical confusion with that disease, including the acquired methylation of MLH1, Lynch-like syndrome, and Familial CRC-Type X. Patients with Lynch syndrome-associated CRCs have a substantially better prognosis, and there is growing evidence that this is due to the generation of immunogenic frameshift peptides as a consequence of defective DNA mismatch repair, and an effective immune response to the tumor.     

Population‐based screening for Lynch syndrome in Western Australia

We showed earlier that routine screening for microsatellite instability (MSI) and loss of mismatch repair (MMR) protein expression in colorectal cancer (CRC) led to the identification of previously unrecognized cases of Lynch syndrome (LS). We report here the results of screening for LS in Western Australia (WA) during 1994–2012. Immunohistochemistry (IHC) for loss of MMR protein expression was performed in routine pathology laboratories, while MSI was detected in a reference molecular pathology laboratory. Information on germline mutations in MMR genes was obtained from the state's single familial cancer registry. Prior to the introduction of routine laboratory‐based screening, an average of 2–3 cases of LS were diagnosed each year amongst WA CRC patients. Following the implementation of IHC and/or MSI screening for all younger (<60 years) CRC patients, this has increased to an average of 8 LS cases diagnosed annually. Based on our experience in WA, we propose three key elements for successful population‐based screening of LS. First, for all younger CRC patients, reflex IHC testing should be carried out in accredited pathology services with ongoing quality control. Second, a state‐ or region‐wide reference laboratory for MSI testing should be established to confirm abnormal or suspicious IHC test results and to exclude sporadic cases by carrying out BRAF mutation or MLH1 methylation testing. Finally, a state or regional LS coordinator is essential to ensure that all appropriate cases identified by laboratory testing are referred to and attend a Familial Cancer Clinic for follow‐up and germline testing.     

Recent advances in radiotherapy treatment planning

Radiation treatment planning is currently in a state of rapid change. Dissatisfaction with past planning technology stems from the growing realization that: (1) Increases in the local regional tumor control rate will increase the cure rate in many malignancies. (2) Even at the best treatment centers geometric tumor misses are commonplace. (3) Traditional constraints on treatment techniques, originally imposed for simplicity and reproducibility, are no longer necessary, and can result in suboptimal treatment. (4) Treatment plans judged "optimal" in two dimensions may be far from optimal when viewed over the entire treatment volume. (5) Lack of treatment reproducibility is also commonplace, and can be demonstrated to adversely affect treatment outcome. On the positive side, recent developments in computer graphics, image processing, radiation physics, and radiation biology are now making it possible to define, design, and deliver sophisticated 3D radiation treatments. However, because many of these technologies are being developed for other disciplines, their applicability to radiation therapy treatment planning is not widely appreciated. We outline the current status and new developments in radiation therapy treatment planning.     

Lynch syndrome: barriers to and facilitators of screening and disease management

Background

Neurofibroma occurs as isolated or multiple lesions frequently associated with neurofibromatosis type 1 (NF1), a common autosomal dominant disorder affecting 1 in 3500 individuals. It is caused by mutations in the NF1 gene, which comprises 60 exons and is located on chromosome 17q11.2. NF1 is a fully penetrant gene exhibiting a mutation rate some 10-fold higher compared with most other disease genes. As a consequence, a high number of cases (up to 50%) are sporadic. Mutation detection is complex due to the large size of the NF1 gene, the presence of pseudogenes and the great variety of lesions.

Methods

110 patients with at least two neurofibroma lesions recorded in the files of the Pathology Department of the University of Modena during the period 1999-2010, were included in this study. Through interviews and examination of clinical charts, pedigrees were drawn for all patients who were affected by at least two neurofibromas. We attempted to delineate the clinical features of NF1 and the mutational spectrum in the cohort of 11 NF1 families identified. For each proband, the whole coding sequence and all splice sites were studied for mutations, either by the protein truncation test (PTT), or, more frequently, by denaturing high performance liquid chromatography (DHPLC). Two GIST tumors of NF1 patients were tested for somatic NF1 mutations.

Results

NF1 germline mutations were identified in 7 (68%) patients. A novel mutation, c.3457_3460delCTCA in exon 20, was detected in two unrelated patients and was associated with different clinical features. No NF1 somatic mutations were detected in the GIST tumors. A wide phenotypic and genotypic variability was registered, both in the spectrum of skin lesions and visceral neoplasms, even among members of the same family who had different clinical manifestations. A proclivity to multiple tumors arising in the same subject, and a higher tumor burden per family were the most relevant findings observed in patients affected with the NF1 mutation.

Conclusions

We report a novel NF1 mutation and we contribute data for the refinement of the NF1 genotype-phenotype spectrum.     

异常淋巴细胞克隆型高嗜酸细胞综合征的研究进展

 【摘要】　异常淋巴细胞克隆型高嗜酸细胞综合征在临床上罕见,异常克隆的淋巴细胞在其发生、发展中起重要作用。近年来对异常淋巴细胞克隆型高嗜酸细胞综合征的研究较多,就此进行综述。     

Recent advances in biology and treatment of myelodysplasia.

The myelodysplastic syndromes are clonal hematopoietic stem cell disorders characterized by varying degrees of pancytopenia and often a progression to acute myeloid leukemia. Recent evidence has linked myelodysplastic syndromes to environmental and occupational genotoxic exposure. Specific cytogenetic abnormalities are well described in myelodysplastic syndromes and have been demonstrated to be useful diagnostic and prognostic tools. Activation of protooncogenes such as ras and fms have also been noted in myelodysplastic syndromes; however, their contribution to the pathogenesis of the syndrome remains to be determined. Aggressive leukemia-like induction therapy, differentiating agents (low-dose cytarabine, 13-cis-retinoic acid) have had little impact on overall survival in myelodysplastic syndromes. The recombinant hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor) may be of significant benefit to patients with myelodysplastic syndromes, although it remains to be determined whether they will have a substantial impact on survival. Allogeneic bone marrow transplantation is the only potentially curable treatment of myelodysplastic syndromes. The advanced age of these patients as well as the lack of histocompatible donors restricts this modality to only a small proportion of patients.     

胃癌的诊断与治疗进展

近年来有关胃癌的基础和临床科研均取得一定的成果,作者就此对胃癌的诊断和治疗进展做一综述.     

New advances in screening and treatment of ovarian cancer

Advances were recently observed in the early diagnosis and treatment of epithelial ovarian cancer. Molecular biology, particularly proteomics, seems to offer interesting results concerning the screening of ovarian cancer. The treatment of this tumor is based on surgery and adjuvant chemotherapy. Several studies were recently published concerning the interest and results of para-aortic lymphadenectomy and interval debulking surgery (after neo-adjuvant chemotherapy) in the surgical management of ovarian cancer. Advances in chemotherapy and new drugs will be also studied in this paper.