Lynch综合征相关肿瘤概述

Lynch综合征是一种已被公认的遗传性肿瘤综合征,是引起遗传性结直肠癌最常见的病因,也是目前唯一已知的遗传性子宫内膜癌的病因,Lynch综合征相关肿瘤还包括卵巢癌、胃癌、尿路上皮癌和小肠癌等。虽然已明确Lynch综合征的发病机制是错配修复缺陷和微卫星不稳定性,但是近年来其诊断和分子发病机制方面不断有新的进展,提示不同的错配修复基因缺陷对应着不同的Lynch综合征相关肿瘤及不同的发病率,对患者的监测产生着新的影响,治疗手段也在不断丰富和改进,如利用微卫星不稳定性的免疫效应治疗Lynch综合征相关肿瘤已取得了积极的成果。介绍Lynch综合征的遗传学特征、筛查诊断、其相关肿瘤的临床病理特征及治疗,重点阐述该综合征的最新进展。     

Lynch综合征相关子宫内膜癌新进展

子宫内膜癌是女性Lynch综合征患者最常见的肠外肿瘤,与散发性子宫内膜癌不同,该病是常染色体显性遗传病,病因及发病机制是错配修复基因(MLH1、MSH2、MSH6及PMS2)的突变或异常表达。患者发病年龄年轻,病理类型多样,包括子宫内膜样癌、透明细胞癌、浆液性癌、未分化癌或癌肉瘤等。由于该病再次发生肿瘤的风险较高,危害大,因此及时治疗Lynch综合征相关的子宫内膜癌是有效预防该类患者再次发生肿瘤的关键。就Lynch综合征相关子宫内膜癌的病因、发病机制、临床病理特征及诊断、治疗和筛查新进展进行综述。     

Lynch综合征相关性妇科恶性肿瘤的研究进展

Lynch综合征(lynch syndrome)是一种DNA错配修复基因突变所导致的常染色体显性遗传病。Lynch综合征的女性患者,一生中发生子宫内膜癌的风险是40%~60%,而发生卵巢癌的风险是7%~12%。近年来发达国家采用免疫组织化学、微卫星不稳定性和基因检测等相结合的分子诊断方法 ,弥补了单一临床诊断标准存在漏诊的不足,大大地提高了Lynch综合征的诊断率,并已通过对患者随访和预防性手术减少了妇科恶性肿瘤的发生。我国对Lynch综合征相关妇科恶性肿瘤还未引起足够重视,目前仍沿用临床诊断,尚缺乏发病情况的流行病学统计。     

Lynch综合征相关性子宫内膜癌的研究进展

Lynch综合征相关性子宫内膜癌是一种遗传性肿瘤,因错配修复基因突变所致,在Lynch综合征女性患者中发生率最高,但因对疾病的认识不足及相关筛查方式的有限,漏诊率较高.目前推荐免疫组织化学和微卫星不稳定性分析的联合筛查模式,以及二代测序的出现,均可提高确诊率.规范筛查流程可尽早筛查出Lynch综合征相关性肿瘤,使患者及...     

Lynch综合征与妇科肿瘤

Lynch综合征又称遗传性非息肉性结直肠癌综合征(hereditary non-polyposis colorectal cancer,HNPCC),属常染色体显性遗传性疾病,由DNA错配修复(mismatch repair,MMR)基因突变引起。Lynch综合征根据有无肠外肿瘤分为Ⅰ型（无肠外肿瘤）和Ⅱ型（有肠外肿瘤）,Ⅰ型仅表现为结直肠癌;Ⅱ型除结直肠癌外,还表现为多样性肠外肿瘤,常见有子宫内膜癌和卵巢癌,在某些Lynch综合征Ⅱ型患者的家族中还有其他恶性肿瘤的发生,如输尿管和肾盂的移行细胞癌、胃癌、小肠癌、胰腺癌、甲状腺癌、脑肿瘤、皮肤癌等。在子宫内膜癌患者中,约5％的患者与遗传因素有关,其中Lynch综合征占大多数[1];在卵巢癌患者中,5％～10％的患者与遗传有关,其中BRCA1、BRCA2基因突变引起的遗传性乳腺癌-卵巢癌综合征(HBOCS)和Lynch综合征Ⅱ型占大多数。目前,有关Lynch综合征相关性结直肠癌的发病过程和分子学特征研究较多,而Lynch综合征相关性妇科肿瘤的研究较少。本文对Lynch综合征相关性子宫内膜癌和卵巢癌的诊断、发病风险、临床病理特征、筛查及预防进行综述。     

曼彻斯特国际共识小组对Lynch综合征相关妇科癌症管理指南的解读

Lynch 综合征是一种常染色体显性遗传性癌症综合征,是由于 DNA 错配修复 (mismatch repair, MMR) 相关基因MLH1、MSH2、MSH6、PMS2的致病性突变所致,包括结直肠癌、子宫内膜癌及卵巢癌等[1-2].对Lynch综合征的诊断不仅可以为患者自身的治疗、随访及监测等提供有效的指导,而且可...     

子宫内膜癌相关Lynch综合征的研究进展

子宫内膜癌相关的Lynch综合征是常见的遗传性癌症综合征,应在内膜癌患者中针对Lynch综合征进行普遍筛查。目前以病理免疫组化、微卫星不稳定等方案联合检测为最常见的筛查策略,以靶位点的基因测序为诊断金标准。对于内膜癌患者及其亲属提供有关Lynch综合征的遗传咨询和检测,结合针对性的筛查、随访和治疗,可显著降低相关癌症的风险。我国内膜癌的发病率呈上升趋势,目前亟待结合本国国情制订出成本效益最优化的内膜癌相关Lynch综合征诊治方案,进一步提高我国内膜癌相关Lynch综合征的筛选方法和诊治水平。     

微卫星不稳定性与卵巢癌相关性研究

微卫星不稳定性(MSI)是由于复制错误(RER)引起的微卫星(MS)长度的改变,在真核生物基因组中广泛存在。微卫星不稳定性与多种肿瘤如结直肠癌、胃癌、乳腺癌、子宫内膜癌和卵巢癌相关。卵巢癌中错配修复(MMR)基因表达缺陷有助于形成微卫星不稳定性,50%以上高频率MSI(MSI-H)的发生可能由于MMR功能缺陷,尤其是hMLH1启动子过度甲基化。患两种恶性肿瘤的患者其MSI-H的发生更普遍。MSI-H与分化低和临床分期高呈显著相关。表现为微卫星不稳定性的患者有预后不良的趋势。综述微卫星不稳定性与MMR基因表达缺陷、卵巢癌的不同病理类型、顺铂耐药及预后的相关性。     

微卫星不稳定性与卵巢癌相关性研究

微卫星不稳定性(MSI)是由于复制错误(RER)引起的微卫星(MS)长度的改变,在真核生物基因组中广泛存在.微卫星不稳定性与多种肿瘤如结直肠癌、胃癌、乳腺癌、子宫内膜癌和卵巢癌相关.卵巢癌中错配修复(MMR)基因表达缺陷有助于形成微卫星不稳定性,50%以上高频率MSI(MSI-H)的发生可能由于MMR功能缺陷,尤其是hMLH1启动子过度甲基化.患两种恶性肿瘤的患者其MSI-H的发生更普遍.MSI-H与分化低和临床分期高呈显著相关.表现为微卫星不稳定性的患者有预后不良的趋势.综述微卫星不稳定性与MMR基因表达缺陷、卵巢癌的不同病理类型、顺铂耐药及预后的相关性.     

子宫内膜癌微卫星不稳定性研究新进展

继雌激素持久刺激和基因异常后,微卫星的不稳定状态被认为是子宫内膜恶性肿瘤形成的第三因素,其由功能异常的DNA错配修复系统引起。近年来发现微卫星不稳定性与肿瘤关系密切,是肿瘤形成的一种重要因素,但微卫星不稳定性在检测方法、肿瘤形成中的作用和肿瘤治疗等方面尚无统一认识,特别是在子宫内膜癌中,微卫星不稳定性应用存有很大争议,本文就近年来相关研究进行总结。     

Lynch syndrome in women less than 50 years of age with endometrial cancer

OBJECTIVE: To estimate the frequency of mismatch repair deficiencies associated with hereditary nonpolyposis colorectal cancer, or Lynch syndrome, in women less than age 50 with endometrial cancer. METHODS: Consecutive patients less than age 50 diagnosed with endometrial adenocarcinoma were identified. Available pathologic specimens were freshly sliced, and protein expression for MLH1, MSH2, MSH6, and PMS2 was evaluated by immunohistochemistry. Slides were scored on a semiquantitative method with complete absence of any of the four proteins suggesting a deficiency. All results were confirmed by microsatellite instability testing. RESULTS: Sixty-one pathology specimens were analyzed. Twenty-one (34%) of the tumors had absence of staining of at least one of the four mismatch repair proteins determined by immunohistochemistry and confirmed by microsatellite instability testing. Obese patients were less likely than nonobese patients to have a mismatch repair deficiency (21% versus 59%, respectively). Non-obese patients had a relative risk for a mismatch repair deficiency of 5.5 (95% confidence interval 1.6-19.1; P=.01). CONCLUSION: Many women diagnosed with endometrial cancer before age 50 will have a mismatch repair deficiency discovered by immunohistochemistry and microsatellite instability testing. A number of young women diagnosed with endometrial cancer will require further genetic testing for mismatch repair mutations. LEVEL OF EVIDENCE: III.     

林奇综合征相关卵巢癌新进展

林奇综合征（Lynch syndrome,LS）是一种常染色体显性肿瘤综合征,是由DNA错配修复（MMR）基因中的一个胚系突变使细胞具有高微卫星不稳定表型（MSI-H）的超突变或缺乏MMR蛋白表达从而引起肿瘤的发生。突变携带者具有罹患结直肠癌、子宫内膜癌和卵巢癌等一系列恶性肿瘤的高风险。虽然LS中最常见的是结直肠癌,但约有60％的LS首发癌为妇科恶性肿瘤（如子宫内膜癌、卵巢癌等）,且其被诊断年龄较早、组织病理学大多为子宫内膜样或非浆液性类型、总体存活率良好。因此及时发现LS相关卵巢癌（LSAOC）这一亚类,对于预防LS患者其他肿瘤的发生,提高LS患者的生存率具有重要意义。目前关于LS的发病机制、组织病理学等方面不断有新的探索,现就LSAOC的早期诊断、组织病理学、筛查及降低风险方案的最新进展进行综述。     

Hereditary Endometrial Cancer: Lynch Syndrome

Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]), Cowden syndrome (CS), and Peutz-Jeghers syndrome (PJS) are hereditary diseases with an increased risk for endometrial cancer. Lynch syndrome is the most frequent disease associated with hereditary endometrial cancer. Lynch syndrome is autosomal dominant disorder caused by germ-cell mutation of DNA mismatch repair genes. Patients with Lynch syndrome have a higher risk of endometrial cancer compared with the general population. Thus, these patients and their families may develop malignant tumors, including colon and endometrial cancers. The lifetime risk of endometrial cancer in females with Lynch syndrome is particularly high (28-60 %). Lynch syndrome is a typical hereditary tumor associated with endometrial cancer, and elucidation of the oncogenic mechanism is important to understand the characteristics of endometrial cancer, including sporadic endometrial cancer. The Amsterdam II Criteria are used for screening for Lynch syndrome, but some cases of hereditary endometrial cancer do not meet these criteria (masked Lynch syndrome); therefore, patients with a suspected hereditary predisposition, including juvenile-onset and double cancer, should undergo genetic tests in addition to taking of a family history.     

林奇综合征相关子宫内膜癌研究进展

林奇综合征（lynch syndrome,LS）是一种常染色体显性遗传病,既往称为遗传性非息肉病性结直肠癌（hereditary nonpolyposis colorectal cancer,HNPCC）,是由DNA错配修复（mismatch repair,MMR）基因MLH1、MSH2、MSH6和PMS2的胚系突变引起。LS患者有多种癌变倾向、发病低龄化及家族易感性,可同时或异时发生结直肠癌、子宫内膜癌（endometrial cancer,EC）、卵巢癌、胃癌和乳腺癌等,女性患者中EC与之最为密切,目前我国对于LS相关EC（LS-EC）认识尚不足,并未形成完整的诊疗标准或指南。为提高对LS-EC的认识,综述LS-EC的分子机制、临床病理特征、筛查及诊断、临床治疗手段、预防等。     

Microsatellite instability and genetic alterations in ovarian cancer

Inactivation of the mismatch repair system (MMR) leads to the accumulation of mutations, particularly in highly repeated sequences (microsatellite). The resulting microsatellite instability can profoundly affect the cellular behaviour, since many genes playing important roles in the mechanisms of signal transduction, apoptosis, DNA repair and cell cycle control can be altered in tumors presenting microsatellite instability. Germline mutations in MMR genes are associated with hereditary non polyposis colon cancer. Microsatellite instability and the associated frameshift mutations in genes have been well described in sporadic colon, gastric and endometrium tumors. In this review we collected the data available on the impact of microsatellite instability in ovarian cancer and the possible consequences of this instability to the presence of mutations in genes containing in their coding regions repeated nucleotides and to the response of these tumors to chemotherapy.     

Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients

ObjectiveLynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV.Methods341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13–12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified.ResultsTwenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total).ConclusionsSince double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.     

RAS/RAF mutation and defective DNA mismatch repair in endometrial cancers

OBJECTIVE: Defective DNA mismatch repair is a common genetic abnormality in both colon cancers and endometrial cancers. Cancers with defective DNA mismatch repair have the so-called mutator phenotype and accumulate genetic errors at an increased rate. An early mutational target in cells with defect DNA mismatch repair may be the RAS/RAF pathway. Colon cancers often have KRAS2 mutations and, if not KRAS2 mutations, may have BRAF mutations. This study investigated the spectrum and frequency of mutations in BRAF and KRAS2 in endometrial carcinomas on the basis of mismatch repair status. STUDY DESIGN: Four hundred forty-one patients with endometrial cancer were staged properly and graded and evaluated for mismatch repair status. These patients were then stratified to groups by the degree of microsatellite instability that was observed in their tumors. One hundred forty-six of the selected tumors were then evaluated for KRAS2 and BRAF mutations on the basis of their microsatellite instability. RESULTS: One hundred forty-six endometrioid endometrial cancers were evaluated for KRAS2 and BRAF mutations. Thirty-five cancers (24%) had activating KRAS2 mutations, but only a single BRAF mutation was identified in an microsatellite instability-positive cancer. Twenty-four of 81 microsatellite instability high cancers (29.6%) in which the MLH1 repair gene was methylated had KRAS2 mutations. When compared with the other groups, this finding approached statistical significance (P=.06). KRAS2 mutation status was associated with increasing age at diagnosis (P=.02). CONCLUSION: Despite many similarities between colon and endometrial cancers, the mechanism of the development of endometrial cancers appears to be different from colon cancers in that BRAF is not affected by a mismatch repair problem, because only KRAS2 mutations were seen. In addition, increasing age appears to lead to an increased likelihood that such a mutation will occur.     

Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for lynch syndrome

Objective

Determine factors impacting the uptake of genetic counseling and results of genetic testing following universal tumor testing for Lynch syndrome in patients with endometrial cancer.

Methods

The study population consisted of two unselected cohorts of endometrial cancer patients, 408 identified retrospectively and 206 identified prospectively. Immunohistochemistry for mismatch repair protein expression and/or microsatellite instability analysis was performed on these tumors. MLH1 methylation analysis was performed on tumors with loss of MLH1 protein. Tumor studies were considered suggestive of Lynch Syndrome if they showed immunohistochemical loss of MSH2, MSH6 or PMS2, loss of MLH1 without MLH1 promoter methylation, and/or microsatellite instability. Participants with suggestive tumor studies were contacted and offered genetic counseling and testing.

Results

In the retrospective cohort, 11% had tumor studies suggestive of Lynch syndrome, and 42% was seen for genetic counseling. A germline mutation was detected in 40%, and one had a variant of uncertain significance. In the prospective cohort, 8.7% of patients had tumor testing suggestive of Lynch syndrome; 72% were seen for genetic counseling. Germline mutations were found in 40%, and one had a variant of uncertain significance. Common challenges included timing of re-contact, age, perceived lack of relevance, inability to travel and limited insurance coverage.

Conclusions

There are several barriers to genetic counseling and testing follow-up after universal tumor testing, and uninformative genetic test results present a management challenge. It is important to consider these limitations when implementing an approach to screening endometrial cancer patients for Lynch syndrome.     

Molecular carcinogenesis of endometrial cancer

In 1983, Bokhman proposed a dualistic model of endometrial tumorigenesis based on the clinical observations and clinicopathologic correlations. The majority of endometrial cancers (approximately 70-80%), designated as type I carcinomas, follow the estrogen-related pathway. Histologically, most of the type I tumors seem to arise in the background of hyperplastic endometrium, show an endometrioid differentiation, and are of low grade. Clinically, they are overall characterized by a favorable behavior. Another 10-20% of endometrial cancers, designated as type II carcinomas, follow the estrogen-unrelated pathway and arise in the background of atrophic endometrium. Type II tumors usually occur at an older age, approximately 5-10 years later than type I tumors. They are typically high-grade carcinomas of nonendometrioid differentiation, most frequently serous, less frequently clear cell. Type II carcinomas behave as an aggressive clinical course and poor prognosis. This dualistic model was subsequently supported by the molecular studies, approximately a decade later. At present, endometrioid and serous carcinoma, which represent the major phenotypes of types I and II endometrial carcinomas, respectively, are characterized by distinctive types of genetic instability and molecular alterations. In endometrioid (type I) carcinoma, four major genetic changes are responsible for the tumorigenesis, i.e. silencing of PTEN tumor suppressor gene, presence of microsatellite instability due to alterations of the mismatch repair genes, mutation of K-ras protooncogene, and alteration of beta-catenin gene. On the other hand, p53 mutation and overexpression of Her2/neu oncogene are two major genetic alterations in serous and clear cell (type II) carcinomas. However, like in any model, there is evidence for exceptions. Many endometrial carcinomas are in the gray zone with overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II endometrial cancers. Finally, a small group of endometrial carcinoma is noted to be hereditary. It is known as the most common extracolonic malignancy in hereditary nonpolyposis colorectal cancer (Lynch syndrome), an autosomal dominantly inherited disorder of cancer susceptibility. Inactivation of the mismatch repair genes MSH2 and MSH6 seems to play a central role in the tumorigenesis.     

林奇综合征与妇科肿瘤

林奇综合征（Lynch syndrome）又称为遗传性非息肉性结直肠癌综合征（HNPCC）,属于常染色体显性遗传性疾病,是最常见的结直肠癌遗传形式。林奇综合征患者常会患有多种肿瘤,其中子宫内膜癌及卵巢癌与其关系最为密切,可以视为林奇综合征的“前哨”肿瘤。在诊断患有林奇综合征的女性中,其患子宫内膜癌的终生风险（60%）会高于患结直肠癌的风险。结合临床表现标准及肿瘤分子学评估可以对其进行高效的诊断。在林奇综合征的女性患者中,应每1～2年（而不是每年）进行子宫内膜活检,在生育结束后行预防性手术可以起到有效的筛查及预防作用。对林奇综合征及其相关的子宫内膜癌及卵巢癌不断有新的研究进展,主要对林奇综合征的诊断、相关的子宫内膜癌及卵巢癌进行综述。