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。     

子宫内膜癌中错配修复(MMR)蛋白表达缺失筛查Lynch综合征及其临床病理特点

目的:通过分析比较子宫内膜癌患者的错配修复(MMR)蛋白表达缺失的情况,研究其与临床标准诊断之间的关系,以及MMR蛋白表达缺失者的临床病理特征。方法:收集北京大学第一医院2011年12月至2015年7月收治的313例子宫内膜癌患者的临床资料,免疫组化法分析子宫内膜癌组织中MMR蛋白(MLH1/MSH2/MSH6/PMS2)表达情况。结果:临床诊断或可疑的Lynch综合征22例(7.0%),存在MMR表达缺失者49例(15.7%)。临床诊断或可疑Lynch的患者中,存在MMR表达缺失者的比例明显升高(P=0.011),其中主要是MSH6表达缺失存在差异(P=0.004)。MSH2表达缺失和MSH6表达缺失的患者中合并高血压的比例更低(P=0.002,P=0.045)、淋巴结转移的比例更高(P=0.025,P=0.020)、肿瘤分化差(P=0.030,P=0.010);MSH6表达缺失的患者,相对年龄更小(P=0.021)。结论:免疫组化检测MMR蛋白表达缺失在诊断或可疑Lynch综合征患者中的比例更高,可用于辅助进行Lynch综合征的筛查及诊断。MMR蛋白表达缺失与患者低龄、存在淋巴结转移、肿瘤分化不良等临床病理特征相关。     

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...     

MSH2基因13号外显子移码突变致Lynch综合征相关子宫内膜癌一例

子宫内膜癌是女性常见的恶性肿瘤之一,绝大部分子宫内膜癌为散发型,只有2%为遗传型,遗传型子宫内膜癌也称为Lynch综合征相关性子宫内膜癌(LS-EC)。本例患者43岁,因子宫下段赘生物活检提示子宫内膜低分化腺癌,行子宫内膜癌根治性手术,因肿瘤位于子宫下段,且病理特征提示子宫内膜样腺癌,因存在多个高危因素故行Lynch综合征筛查。根据2019年Manchester国际共识,妇科肿瘤筛查Lynch综合征的流程明确,首先采用免疫组化法检测丢失的蛋白,发现潜在的突变基因,最终通过高通量测序(NGS)技术确诊为MSH2基因13号外显子E701fs移码突变导致的LS-EC。     

子宫内膜癌错配修复蛋白表达与临床病理特征的关系分析

目的探讨错配修复(mismatch repair, MMR)蛋白在子宫内膜癌组织中的表达及其与临床病理特征的关系。方法回顾性分析2013年1月至2018年1月在首都医科大学大兴教学医院行全子宫切除术并经病理诊断的81例子宫内膜癌患者的临床病理资料,采用免疫组织化学检测MSH2、MSH6、MLH1、PMS2表达,并分析其与患者预后指标的关系。结果 81例子宫内膜癌患者中,MMR蛋白总表达缺失率为14.8%(12/81),其中MLH1/PMS2配对表达缺失率最高(66.7%,8/12),MSH2/MSH6配对表达缺失次之(16.7%,2/12),MSH6或PMS2单独表达缺失最少(8.3%,1/12)。MMR表达缺失组与MMR表达正常组在脉管内癌栓、淋巴结转移、累及子宫下段、临床FIGO分期进行比较,差异均有统计学意义(P 0.05);而在患者年龄、肿瘤分化程度、组织学类型、浸润深度及有无复发比较,差异均无统计学意义(P0.05)。结论 MMR蛋白表达异常可辅助用于初步筛选子宫内膜癌相关Lynch综合征患者,并有助于子宫内膜癌的早期筛查和早期诊断。     

“Lynch综合征相关妇科肿瘤监管的曼彻斯特国际共识”要点解读

正Lynch综合征(Lynch syndrome,LS)是一组常染色体显性遗传的癌症综合征,主要包括结直肠癌(colorectal cancer,CRC)、子宫内膜癌(endometrial cancer,EC)以及卵巢癌(ovarian cancer,OC)[1]。LS的发病根源是由于细胞DNA的错配修复(MMR)系统中的MLH1、MSH2、MSH6和PMS2的基因突变,其阻碍了细胞DNA合成过程中的错配修复[2]。早期及时诊断可以对癌症的预测及下一步治疗产生影响。目前,已证实LS患者进行CRC监管可以获得很好的生存获益[3],而国际上LS相关CRC监管的临床指南,并不完全适合妇科肿瘤。在女性中,LS的首发肿瘤多为EC,而且由于子宫内膜癌的前驱症状较明显,临床多早期发现,早     

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。     

子宫内膜癌组织错配修复基因MMR表达及其临床意义

目的:通过检测子宫内膜癌组织错配修复(MMR)蛋白表达缺失情况,探讨错配修复基因在子宫内膜癌中的临床意义。方法:回顾分析北京大学人民医院2018年5月至2019年7月收治的101例子宫内膜癌患者的完整临床病理资料。免疫组化法分析子宫内膜癌组织中MMR蛋白(MSH2、MSH6、MLH1、PMS2)及ER、PR、Ki67表达情况。结果:101例子宫内膜癌中MMR、MSH2、MSH6、MLH1、PMS2蛋白表达缺失率分别为40.6%(41/101)、8.9%(9/101)、10.9%(11/101)、14.9%(15/101)、31.7%(32/101)。MLHl/PSM2及MSH2/MSH6联合缺失率分别为13.9%(14/101)及4.0%(4/101)。BMI<24kg/m~2与MSH2表达缺失相关(P<0.05),24kg/m~2≤BMI<28kg/m~2与PMS2表达缺失相关(P<0.05);内科合并症(高血压病、糖尿病等)与MLH1表达缺失相关(8.2%vs 24.3%,P<0.05)。肌层浸润深度≥1/2与MMR、MSH6、MLH1及PMS2表达缺失相关(P<0.01)。肿瘤直径≥2cm与MMR及PMS2表达缺失相关(P<0.01)。结论:MMR蛋白表达缺失与预后不良相关。肿瘤组织MMR蛋白尤其是MLH1/PMS2检测有助于识别预后不良患者,特别是Lynch综合评估后进行辅助治疗,有助于改善预后。     

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。     

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。     

林奇综合征患者子宫内膜癌及卵巢癌的筛查与预防

患有林奇综合征（Lynch syndrome,LS）的妇女终生患子宫内膜癌和卵巢癌风险大幅增加。而子宫内膜癌或卵巢癌可以是LS患者的首发恶性肿瘤,也可以是第二原发恶性肿瘤。LS相关子宫内膜癌主要类型是子宫内膜样腺癌。近年来,有关LS相关子宫内膜癌及卵巢癌的筛查研究较少,主要是通过门诊子宫内膜活检、微卫星高不稳定性（microsatellite instability-high,MSI-H）状态错配修复（mismatch repair,MMR）蛋白突变及基因检测来识别癌前病变和早期癌症。而在预防方面主要是使用口服避孕药,以及预防性手术切除子宫和卵巢。LS女性患子宫内膜癌终生风险为40%~60%,患卵巢癌的终生风险为4%~24%。因此,对LS女性患者进行子宫内膜癌及卵巢癌的早期筛查和预防有重要意义。     

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.     

Mismatch repair protein deficiency in endometriosis: Precursor of endometriosis-associated ovarian cancer in women with lynch syndrome

ObjectiveWe aimed to elucidate the pathogenesis of ovarian cancer through the loss of mismatch repair (MMR) proteins in women with Lynch syndrome (LS) in this report.Case reportTwo women with LS underwent surgery for synchronous endometrial cancer and ovarian cancer. In both cases, immunohistochemical examination showed concomitant MMR protein deficiency in endometrial cancer, ovarian cancer, and contiguous ovarian endometriosis. In Case 1, the macroscopically normal ovary included multiple endometrioses with MSH2 and MSH6 expression, and FIGO grade 1 endometrioid carcinoma and contiguous endometriosis without MSH2 and MSH6 expression. In Case 2, all endometriotic cells contiguous with carcinoma in the lumen of the ovarian cyst showed loss of the expression of MSH2 and MSH6.ConclusionOvarian endometriosis with MMR protein deficiency may progress to endometriosis-associated ovarian cancer in women with LS. Diagnosing endometriosis in women with LS during surveillance is important.     

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。     

Synchronous occult cancers of the endometrium and fallopian tube in an MSH2 mutation carrier at time of prophylactic surgery

BackgroundWomen with Lynch syndrome have a 40 to 60% lifetime risk of endometrial cancer and a 10 to 12% lifetime risk of ovarian cancer and may consider prophylactic gynecological surgery as an option for risk reduction.CaseWe report a case of synchronous primary cancers of the endometrium and fallopian tube diagnosed at time of prophylactic surgery in an MSH2 mutation carrier.ConclusionRisk-reducing gynecological surgery in Lynch syndrome must include complete removal of the fallopian tubes in addition to the ovaries and endometrium, followed by careful pathological review. Prospective studies are needed to clarify the incidence of occult primary carcinoma of the fallopian tube among female MMR mutation carriers undergoing prophylactic surgery.     

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.     

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.