Durno C, Aronson M, Bapat B, Cohen Z, Gallinger S
Division of Gastroenterology and Clinical Nutrition, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, Ontario, Canada M5G 1X8.
Gut. 2005 Aug;54(8):1146-50. doi: 10.1136/gut.2005.066092. Epub 2005 Apr 21.
Colorectal cancer is extremely rare in childhood. Published case series reporting children and adolescents with colorectal cancer have not focused on the underlying genetic aspects of the tumour or genetic susceptibility of the families.
We examined a cohort of patients with early onset colorectal cancer to determine whether a specific genetic predisposition could be elucidated. In particular, we focused on whether DNA mismatch repair gene deficiency which causes hereditary non-polyposis colorectal cancer (HNPCC) could be elucidated.
Patients with colorectal cancer </=24 years of age were identified from a database at the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital, Toronto. Detailed pedigrees were ascertained from the proband or parents. Tumours were tested for microsatellite instability, a hallmark of HNPCC. Germline mismatch repair gene mutations (MSH2 and MLH1) were sought in some cases. Clinical data were obtained by chart audit.
Among 1382 probands in our registry, 16 (1%) colorectal cancer patients were 24 years or younger at the time of diagnosis. Microsatellite instability was identified in tumours from eight (73%) of 11 evaluated patients. Germline mutations in mismatch repair genes were identified in six of 12 patients, including MSH2 (n = 3), MLH1 (n = 2), and PMS2 (n = 1). Ten (63%) of 16 families met the Amsterdam criteria for HNPCC. Among these, six were screened for mismatch repair gene mutations and three were found to carry MSH2 or MLH1 germline mutations. Location of the colorectal cancers included rectum/sigmoid (n = 9), splenic flexure (n = 2), hepatic flexure (n = 3), and caecum (n = 2). Forty four per cent (7/16) of these young cases developed additional malignancies (gastrointestinal (n = 8) and extraintestinal (n = 4)) during follow up (mean 12.8 (SD 12.4) years (range 0.08-30)).
Patients with early onset colorectal carcinoma often have an inherited predisposition to the disease. Tumours with high frequency microsatellite instability and germline mutations of mismatch repair genes are sufficiently common in this patient population that they should be considered, even though family histories may not satisfy the stringent Amsterdam criteria for HNPCC. Young colorectal cancer patients are at increased risk of developing second gastrointestinal and extraintestinal malignancies.
结直肠癌在儿童时期极为罕见。已发表的报告儿童和青少年结直肠癌的病例系列研究并未聚焦于肿瘤的潜在遗传因素或家族的遗传易感性。
我们研究了一组早发性结直肠癌患者，以确定是否能阐明特定的遗传易感性。特别是，我们关注是否能阐明导致遗传性非息肉病性结直肠癌（HNPCC）的DNA错配修复基因缺陷。
从多伦多西奈山医院家族性胃肠癌登记处的数据库中识别出年龄≤24岁的结直肠癌患者。从先证者或其父母处获取详细的家系图谱。对肿瘤进行微卫星不稳定性检测，这是HNPCC的一个标志。在某些情况下，寻找种系错配修复基因突变（MSH2和MLH1）。通过病历审查获取临床数据。
在我们登记的1382名先证者中，16名（1%）结直肠癌患者在诊断时年龄为24岁或更小。在11名接受评估的患者中，有8名（73%）的肿瘤检测到微卫星不稳定性。在12名患者中有6名检测到错配修复基因的种系突变，包括MSH2（n = 3）、MLH1（n = 2）和PMS2（n = 1）。16个家族中有10个（63%）符合HNPCC的阿姆斯特丹标准。其中，6个家族进行了错配修复基因突变筛查，3个家族被发现携带MSH2或MLH1种系突变。结直肠癌的发病部位包括直肠/乙状结肠（n = 9）、脾曲（n = 2）、肝曲（n = 3）和盲肠（n = 2）。在这些年轻病例中，44%（7/16）在随访期间（平均12.8（标准差12.4）年（范围0.08 - 30年））发生了其他恶性肿瘤（胃肠道（n = 8）和胃肠道外（n = 4））。
早发性结直肠癌患者通常对该疾病有遗传易感性。在这一患者群体中，具有高频微卫星不稳定性和错配修复基因种系突变的肿瘤非常常见，即使家族史可能不符合HNPCC严格的阿姆斯特丹标准，也应予以考虑。年轻的结直肠癌患者发生第二原发性胃肠道和胃肠道外恶性肿瘤的风险增加。
