Lubbe Steven J, Webb Emily L, Chandler Ian P, Houlston Richard S
Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom.
J Clin Oncol. 2009 May 1;27(13):2238-44. doi: 10.1200/JCO.2008.20.3364. Epub 2009 Mar 23.
Estimating familial colorectal cancer (CRC) risk is clinically important in being able to discriminate between high- and low-risk groups. To quantify familial CRC risks associated with mismatch repair (MMR) deficient and microsatellite stable (MSS) tumors, we analyzed 2,941 population-based cases of CRC.
MMR status in CRCs was established by testing for microsatellite instability (MSI). MUTYH status was assigned by screening for Y165C and G382D variants. Age-specific relative and absolute CRC risks in first-degree relatives (FDRs) were calculated, and the most likely genetic models of familial aggregation were derived.
CRC risks in FDRs were strongly associated with MSI status (MSI, standardized incidence ratio [SIR] = 4.28, 95% CI, 3.51 to 5.17; MSS, SIR = 1.91, 95% CI, 1.73 to 2.11), early-onset disease (MSI patient age < 55 years, SIR = 10.96, 95% CI, 8.32 to 14.17; MSS patient age < 55 years, SIR = 2.3, 95% CI, 1.88 to 2.85), and having more than one affected FDR (MSI, SIR = 10.00, 95% CI, 7.74 to 12.72; MSS, SIR = 2.78, 95% CI, 2.18 to 3.48). The familial aggregation of CRC associated with MSI cancer was parsimonious with dominant model conferring a high CRC risk at early ages. Approximately 69% of the excess familial risk in FDRs can be ascribed to MSS CRC, and although the pattern of familial risk supports recessive susceptibility in addition to MUTYH, the absolute risk of CRC is at best modest.
The results from this analysis should enable an individual's risk of CRC to be more accurately estimated, thus maximizing the value of screening programs. Results also have utility in the design of genetic analyses to identify novel disease alleles.
估计家族性结直肠癌（CRC）风险对于区分高风险和低风险群体具有重要的临床意义。为了量化与错配修复（MMR）缺陷和微卫星稳定（MSS）肿瘤相关的家族性CRC风险，我们分析了2941例基于人群的CRC病例。
通过检测微卫星不稳定性（MSI）确定CRC中的MMR状态。通过筛查Y165C和G382D变体来确定MUTYH状态。计算一级亲属（FDR）中特定年龄的相对和绝对CRC风险，并推导家族聚集最可能的遗传模型。
FDR中的CRC风险与MSI状态密切相关（MSI，标准化发病率比[SIR]=4.28，95%CI，3.51至5.17；MSS，SIR=1.91，95%CI，1.73至2.11）、早发性疾病（MSI患者年龄<55岁，SIR=10.96，95%CI，8.32至14.17；MSS患者年龄<55岁，SIR=2.3，95%CI，1.88至2.85）以及有不止一名受影响的FDR（MSI，SIR=10.00，95%CI，7.74至12.72；MSS，SIR=2.78，95%CI，2.18至3.48）。与MSI癌症相关的CRC家族聚集与显性模型相符，该模型在早年赋予较高的CRC风险。FDR中约69%的额外家族风险可归因于MSS CRC，尽管家族风险模式除了支持MUTYH外还支持隐性易感性，但CRC的绝对风险充其量只是中等。
该分析结果应能更准确地估计个体患CRC的风险，从而使筛查计划的价值最大化。结果在设计基因分析以鉴定新的疾病等位基因方面也具有实用性。
