Peelen T, de Leeuw W, van Lent K, Morreau H, van Eijk R, van Vliet M, Wijnen J, Ligtenberg M, Ginjaar H B, Zweemer R, Menko F, Fodde R, van Ommen G J, Vasen H F, Cornelisse C J, Devilee P
Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Int J Cancer. 2000 Dec 1;88(5):778-82. doi: 10.1002/1097-0215(20001201)88:5<778::aid-ijc15>3.0.co;2-n.
Mutations in the BRCA1 gene cause strongly elevated risks of breast and ovarian cancers but may also confer a 3-fold increased risk for colorectal cancer. To address the relationship between BRCA1 carriership and colorectal tumorigenesis, we studied the genetics of a breast-ovarian cancer family with 7 cases of colorectal cancer. A germline 3938insG mutation in BRCA1 was found in 5 breast-cancer patients, 1 with ductal carcinoma in situ, ovarian cancer and an adenoma of the colon, and in 4/5 colorectal-cancer patients investigated. However, the youngest patient, diagnosed at age 23, was a non-carrier. Loss of the wild-type BRCA1 allele was observed in 3/3 breast tissues (2 breast carcinomas and 1 ductal carcinoma in situ) but in 0/6 colorectal tissues (5 carcinomas and 1 adenoma), suggesting that BRCA1 loss is not critical for colorectal tumorigenesis. To examine the possibility that an as yet unknown gene linked to BRCA1 was involved in the colorectal cancers, chromosome 17 segregation was studied with 7 polymorphic markers encompassing a 20 cM region including BRCA1. None of these markers showed complete allele sharing among all 5 colorectal-cancer patients studied. Clinical history, mutation analysis and microsatellite instability analysis excluded a role for any of the known colorectal-cancer susceptibility genes. In 4 other Dutch families carrying the same BRCA1 mutation, only 1 colorectal-cancer case was reported, of which the carrier status is unknown.
BRCA1基因的突变会大幅增加患乳腺癌和卵巢癌的风险，但也可能使患结直肠癌的风险增加两倍。为了探究携带BRCA1基因与结直肠癌发生之间的关系，我们研究了一个有7例结直肠癌病例的乳腺癌-卵巢癌家族的遗传学情况。在5名乳腺癌患者中发现了BRCA1基因的种系3938insG突变，其中1名患有原位导管癌、卵巢癌和结肠腺瘤，在接受调查的5名结直肠癌患者中也发现了该突变。然而，最年轻的患者，23岁被诊断出患有癌症，其不携带该突变。在3个乳腺组织样本（2例乳腺癌和1例原位导管癌）中观察到野生型BRCA1等位基因缺失，但在6个结直肠组织样本（5例癌和1例腺瘤）中均未观察到，这表明BRCA1基因缺失对结直肠癌发生并不关键。为了探究是否有一个与BRCA1相关但未知的基因参与了结直肠癌的发生，我们用7个多态性标记对17号染色体进行分离研究，这些标记覆盖了包括BRCA1基因在内的20 cM区域。在所有研究的5名结直肠癌患者中，这些标记均未显示出完全的等位基因共享。临床病史、突变分析和微卫星不稳定性分析排除了任何已知的结直肠癌易感基因的作用。在其他4个携带相同BRCA1突变的荷兰家族中，仅报告了1例结直肠癌病例，其携带状态未知。
