Anagnostopoulos Antonios, McKay Vicky H, Cooper Iris, Campbell Fiona, Greenhalgh Lynn, Kirwan John
*Northwest Coastal, Gynaecological Oncology Network; †Clinical Genetics, Department of Clinical Genetics, Cheshire and Merseyside Regional Clinical Genetics Service Trust; ‡Liverpool Women's Hospital NHS Trust; §University of Liverpool and Royal Liverpool University Hospital; ∥Macmillan Cancer; and ¶Gynaecology Services, Liverpool Women's Hospital NHS Trust, Liverpool, United Kingdom.
Int J Gynecol Cancer. 2017 Jun;27(5):931-937. doi: 10.1097/IGC.0000000000000962.
Lynch syndrome (LS) is an inherited disorder associated with genetic predisposition to endometrial, colorectal, ovarian, and other cancers. There is consensus for the necessity of assessment for LS in view of the established survival benefits for identified patients and affected family members. The debate regarding the best screening policy is far from being concluded.
The aim of this study was to evaluate a realistic protocol for identifying LS families by assessing young women with a diagnosis of endometrial cancer (EC).
Consecutive cases of women with a diagnosis of endometrioid EC younger than 50 years were recruited. A complete 3-generation pedigree was drawn and assessed against the Amsterdam II criteria. Tumor DNA microsatellite instability and immunohistochemistry testing for the expression of mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2 was offered to all patients. MLH1 gene promoter methylation and EPCAM gene deletion testing were also offered where appropriate. Genetic counseling and MMR germline mutation tests were offered in women with abnormal results.
Fifty-eight women were invited, and 38 (65.5%), consented for LS assessment (95% confidence interval CI 53%-78%). A complete data set was obtained in 35 women (60.3%). Lynch syndrome according to clinical and/or molecular characteristics was diagnosed in 8 cases or 22.8% (95% CI 15%-48%). There was no significant difference at the age of women with a diagnosis of LS (median, 45 years; range, 37-48 years) compared with that of the non-LS ones (median, 45 years; range, 31-49 years). Three pathogenic MMR mutations were identified in the 8 cases with a diagnosis of LS, 37.5% (95% CI 5%-72%), estimating an 8.5% (95% CI 1%-19%) mutation prevalence in the study population.
All women with newly diagnosed EC should be assessed for inherited predisposition. Regional policies for assessment should be developed in accordance with available resources. Gynecologists are required to upgrade their skills in order to identify, assess, and counsel patients with suspected or established LS and appropriately refer to clinical genetics.
林奇综合征（LS）是一种遗传性疾病，与子宫内膜癌、结直肠癌、卵巢癌及其他癌症的遗传易感性相关。鉴于已证实对确诊患者及其受影响的家庭成员有生存获益，对LS进行评估的必要性已达成共识。关于最佳筛查策略的争论远未结束。
本研究的目的是通过评估诊断为子宫内膜癌（EC）的年轻女性，来评估一种识别LS家族的实际方案。
招募连续诊断为年龄小于50岁的子宫内膜样EC的女性病例。绘制完整的三代家系图谱，并根据阿姆斯特丹II标准进行评估。对所有患者进行肿瘤DNA微卫星不稳定性检测以及错配修复（MMR）蛋白MLH1、MSH2、MSH6和PMS2表达的免疫组化检测。在适当情况下，还提供MLH1基因启动子甲基化和EPCAM基因缺失检测。对结果异常的女性提供遗传咨询和MMR种系突变检测。
邀请了58名女性，38名（65.5%）同意进行LS评估（95%置信区间CI 53%-78%）。35名女性（60.3%）获得了完整数据集。根据临床和/或分子特征诊断为林奇综合征的有8例，占22.8%（95% CI 15%-48%）。诊断为LS的女性年龄（中位数45岁；范围37-48岁）与非LS女性（中位数45岁；范围31-49岁）相比无显著差异。在8例诊断为LS的病例中鉴定出3个致病性MMR突变，占37.5%（95% CI 5%-72%），估计研究人群中的突变患病率为8.5%（95% CI 1%-19%）。
所有新诊断为EC的女性均应评估其遗传易感性。应根据可用资源制定区域评估政策。妇科医生需要提升技能，以便识别、评估和咨询疑似或确诊为LS的患者，并适当地转诊至临床遗传学部门。
