Genetic Services of Western Australia, King Edward Memorial Hospital, Subiaco, WA, Australia.
Fam Cancer. 2012 Mar;11(1):1-6. doi: 10.1007/s10689-011-9494-2.
We have previously established in a large retrospective study that testing for microsatellite instability (MSI) in colorectal cancer (CRC) from patients aged <60 years was an effective first screen to identify individuals with Lynch syndrome (LS). From these findings, MSI and/or immunohistochemical (IHC) screening was recommended for all newly diagnosed CRC patients aged <60 years in Western Australia, regardless of family history of cancer. In the current study we evaluated the utility of routine MSI/IHC screening by diagnostic pathology laboratories for the detection of previously undiagnosed individuals and families with LS. From January 2009 to December 2010, 270 tumours were tested for MSI and for expression of MLH1, PMS2, MSH2 and MSH6 using IHC. Cases showing MSI and/or loss of expression were also tested for the BRAF V600E hotspot mutation. Seventy cases were found to have MSI, of which 25 were excluded from further investigation as possible LS cases due to presence of the BRAF V600E mutation. The remaining 45 "red flag" cases were eligible for germline testing based on their MSI, IHC and BRAF status. From 31 cases tested to date, 15 germline mutations have been found. Thirteen were from individuals not previously recognized as LS and two were untested members from known LS families. Extrapolation of the mutation incidence (15/31, 48%) to all red flag cases (n = 45) suggests that approximately 22 mutation carriers exist in this cohort. This value approximates the number of CRC cases due to LS that could be expected to arise in the Western Australian population over a two-year period (n = 24), assuming that 1% of all CRCs are due to LS. Although further improvements in workflow can be made, our preliminary findings following the implementation of state-wide routine MSI and IHC testing in Western Australia indicate that the majority of LS cases are being identified.
我们之前在一项大型回顾性研究中已经确定，对年龄<60 岁的结直肠癌（CRC）患者进行微卫星不稳定性（MSI）检测是识别林奇综合征（LS）个体的有效初筛方法。基于这些发现，在澳大利亚西部，所有新诊断为年龄<60 岁的 CRC 患者，无论是否有癌症家族史，都建议进行 MSI 和/或免疫组织化学（IHC）筛查。在目前的研究中，我们评估了诊断病理学实验室常规进行 MSI/IHC 筛查以检测先前未诊断的 LS 个体和家族的实用性。从 2009 年 1 月至 2010 年 12 月，对 270 个肿瘤进行了 MSI 检测和 MLH1、PMS2、MSH2 和 MSH6 的免疫组化表达检测。显示 MSI 和/或表达缺失的病例也检测了 BRAF V600E 热点突变。发现 70 例肿瘤存在 MSI，其中 25 例由于存在 BRAF V600E 突变而被排除在进一步调查之外，可能是 LS 病例。剩余的 45 例“红旗”病例，根据其 MSI、IHC 和 BRAF 状态，符合进行种系测试的条件。迄今为止，已对 31 例病例进行了测试，发现了 15 种种系突变。其中 13 例来自以前未被认为是 LS 的个体，2 例来自已知 LS 家族的未测试成员。将突变发生率（15/31，48%）外推到所有“红旗”病例（n=45），表明在该队列中大约有 22 个突变携带者。这一数值接近在澳大利亚西部人群中在两年内可能发生的由 LS 引起的 CRC 病例数（n=24），假设所有 CRC 中有 1%是由 LS 引起的。尽管在西澳大利亚州实施全州范围内的常规 MSI 和 IHC 检测后，可以进一步改进工作流程，但我们的初步发现表明，大多数 LS 病例正在被识别出来。
