Calabrese Peter, Tsao Jen-Lan, Yatabe Yasushi, Salovaara Reijo, Mecklin Jukka-Pekka, Järvinen Heikki J, Aaltonen Lauri A, Tavaré Simon, Shibata Darryl
Department of Biological Sciences, Program in Molecular and Computational Biology, University of Southern California, Los Angeles, California 90033, USA.
Am J Pathol. 2004 Apr;164(4):1447-53. doi: 10.1016/S0002-9440(10)63231-2.
A pretumor progression model predicts many oncogenic cancer mutations may first accumulate in normal appearing colon. Although direct observations of early pretumor mutations are impractical, it may be possible to retrospectively reconstruct tumor histories from contemporary cancer mutations. To infer when and in what order mutations occur during occult pretumor progression, we examined 14 cancers from individuals with heterozygous germline mutations in DNA mismatch repair (MMR) genes or hereditary nonpolyposis colorectal cancer (HNPCC). Somatic inactivation of the normal allele occurs sometime during a lifetime and results in loss of MMR, elevated mutation rates, and subsequent widespread somatic microsatellite mutations in HNPCC cancers. Patient ages at MMR loss can be estimated because intervals between MMR loss and cancer removal can be inferred from numbers of microsatellite tumor mutations. The relative order of MMR loss during pretumor progression may also be inferred from its collective ages of occurrence. Somatic MMR loss preceded cancer removal by an average of 6.1 years, occurred relatively late in life (average of 41.6 versus 47.7 years at cancer removal), and was a surprisingly late (fifth or sixth) step. Calculations indicate five or six oncogenic mutations could accumulate with relatively normal replication fidelity in normal appearing colon. HNPCC pretumor progression essentially begins from birth and ends with MMR loss, implying elevated mutation rates and tumorigenesis may be unnecessary for most progression.
一种肿瘤前进展模型预测，许多致癌性癌症突变可能首先在外观正常的结肠中积累。尽管直接观察早期肿瘤前突变不切实际，但从当代癌症突变中回顾性重建肿瘤病史或许是可行的。为了推断在隐匿性肿瘤前进展过程中突变发生的时间和顺序，我们研究了14例患有DNA错配修复（MMR）基因杂合种系突变或遗传性非息肉病性结直肠癌（HNPCC）的个体的癌症。正常等位基因的体细胞失活在一生中的某个时候发生，导致MMR丧失、突变率升高，随后在HNPCC癌症中出现广泛的体细胞微卫星突变。由于可以从微卫星肿瘤突变的数量推断MMR丧失与癌症切除之间的间隔，因此可以估计MMR丧失时的患者年龄。肿瘤前进展过程中MMR丧失的相对顺序也可以从其发生的总体年龄推断出来。体细胞MMR丧失发生在癌症切除前平均6.1年，发生时间相对较晚（癌症切除时平均为41.6岁对47.7岁），并且是一个出人意料的晚期（第五或第六）步骤。计算表明，在外观正常的结肠中，五个或六个致癌突变可能以相对正常的复制保真度积累。HNPCC肿瘤前进展基本上从出生开始，以MMR丧失结束，这意味着对于大多数进展而言，升高的突变率和肿瘤发生可能并非必要。
