Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer

被引:101
作者
Young, J [1 ]
Barker, MA
Simms, LA
Walsh, MD
Biden, KG
Buchanan, D
Buttenshaw, R
Whitehall, VLJ
Arnold, S
Jackson, L
Kambara, T
Spring, KJ
Jenkins, MA
Walker, GJ
Hopper, JL
Leggett, BA
Jass, JR
机构
[1] Queensland Inst Med Res, Conjoint Gastroenterol Lab, Herston, Qld 4029, Australia
[2] Queensland Inst Med Res, Human Genet Lab, Herston, Qld 4029, Australia
[3] Okayama Univ, Grad Sch Med & Dent, Dept Surg Gastroenterol, Okayama 7008530, Japan
[4] Univ Melbourne, Ctr Genet Epidemiol, Parkville, Vic 3052, Australia
[5] McGill Univ, Dept Pathol, Montreal, PQ, Canada
关键词
D O I
10.1016/S1542-3565(04)00673-1
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: Recently, an alternative pathway of tumorigenesis has been identified in the colorectum associated with serrated precursor lesions, variable levels of microsatellite instability (MSI-V), and driven in part by activating mutations in the BRAF proto-oncogene (V599E). Somatic BRAF mutations in hereditary nonpolyposis colon cancer (HNPCC) are rarely observed. Here, we discuss their role in the development of other familial colorectal cancers (CRC). We studied non-FAP, non-HNPCC CRC families characterized by tumors that varied in their level of MSI between individual members. Methods: A subset of tumors from a total of 55 collected (25 polyps and 30 cancers) from 43 individuals across 1:1 families underwent pathology review, examination for V599E using allele-specific polymerase chain reaction, and for methylation of the MINT31 CpG island. Results: All MSI-V families met the current revised Bethesda Guidelines and 6 of 11 (55%) met the Amsterdam I criteria. V599E was observed in 12 of :19 (63%) polyps and 14 of 20 (70%) cancers (4 of 4 high MSI, 2 of 4 low MSI, and 8 of :12 stable MSI), a significant increase over HNPCC (0 of :15 or 0%), and unselected CRC (30 of 197 or 15.2%) (P <.05). Eight of the 10 (80%) cancers that underwent analysis showed hypermethylation of MINT31. CRCs showed early age at onset and were more likely to show a serrated architecture than unselected CRCs (P <.05). Conclusions: These data provide evidence that the families described here represent a syndrome of familial CRC that is distinct from HNPCC. High levels of BRAF mutation and MINT31 hypermethylation suggest an origin in the serrated pathway of CRC development.
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页码:254 / 263
页数:10
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