Jenkins Mark A, Baglietto Laura, Dowty James G, Van Vliet Christine M, Smith Letitia, Mead Leeanne J, Macrae Finlay A, St John D James B, Jass Jeremy R, Giles Graham G, Hopper John L, Southey Melissa C
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Victoria, Australia.
Clin Gastroenterol Hepatol. 2006 Apr;4(4):489-98. doi: 10.1016/j.cgh.2006.01.002.
BACKGROUND & AIMS: Cancer risks for mismatch repair gene mutation carriers have been derived almost exclusively using families ascertained owing to their strong cancer family history. These may be overestimates, due to analytic problems, and not generalizable. We estimated average cancer risks for mutations identified in population-based early onset colorectal cancer cases (probands) unselected for family history.
Data were cancer histories and mutation status (carrier, non-carrier, or unknown) of 17 mismatch repair gene mutation carrier probands with colorectal cancer diagnosed before age 45 (8 hMLH1, 4 hMSH2, 4 hMSH6, 1 hPMS2) and their first- and second-degree relatives. We used modified segregation analysis theory, adjusting for the family being ascertained through the proband being an early onset mutation carrier.
Eleven carrier probands (64%) were from families meeting the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. The cumulative risk for colorectal cancer (95% confidence interval) to age 70 was 45% (29%-62%) for men and 38% (19%-51%) for women. Corresponding risks were 67% (47%-84%) and 72% (48%-85%) for any hereditary nonpolyposis colorectal cancer-related cancer. Compared with the general population, colorectal cancer incidence for men was approximately 180-fold higher before age 50, but about the same after age 50. For women, incidence was approximately 100-fold higher before age 50 and 7-fold higher thereafter.
For carriers of the mutations in the mismatch repair genes that cause early onset colorectal cancer, colorectal cancer increases rapidly until age 50, and the incidence decreases to general population levels at older ages.
错配修复基因突变携带者的癌症风险几乎完全是通过因癌症家族史强烈而被确定的家系得出的。由于分析问题，这些风险可能被高估，且不具有普遍性。我们估计了在未根据家族史进行选择的基于人群的早发性结直肠癌病例（先证者）中鉴定出的突变的平均癌症风险。
数据包括17名错配修复基因突变携带者先证者（8名hMLH1、4名hMSH2、4名hMSH6、1名hPMS2）及其一级和二级亲属的癌症病史和突变状态（携带者、非携带者或未知），这些先证者在45岁之前被诊断为结直肠癌。我们使用改良的分离分析理论，并对通过先证者为早发性突变携带者而确定的家系进行了调整。
11名携带者先证者（64%）来自符合遗传性非息肉病性结直肠癌阿姆斯特丹II标准的家系。到70岁时，男性患结直肠癌的累积风险（95%置信区间）为45%（29%-62%），女性为38%（19%-51%）。任何遗传性非息肉病性结直肠癌相关癌症的相应风险分别为67%（47%-84%）和72%（48%-85%）。与一般人群相比，男性在50岁之前结直肠癌发病率大约高180倍，但在50岁之后大致相同。对于女性，发病率在50岁之前大约高10倍，之后高7倍。
对于导致早发性结直肠癌的错配修复基因突变携带者，结直肠癌在50岁之前迅速增加，在老年时发病率降至一般人群水平。
