Gotlieb W H, Friedman E, Bar-Sade R B, Kruglikova A, Hirsh-Yechezkel G, Modan B, Inbar M, Davidson B, Kopolovic J, Novikov I, Ben-Baruch G
Division of Gynecologic Oncology, Sheba Medical Center, and Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel.
J Natl Cancer Inst. 1998 Jul 1;90(13):995-1000. doi: 10.1093/jnci/90.13.995.
Germline mutations in the BRCA1 and BRCA2 genes are known to be associated with an increased risk of breast and epithelial ovarian cancers. Two specific mutations, 185delAG-BRCA1 and 6174delT-BRCA2, have been detected in a substantial proportion (20%-60%) of unselected Ashkenazi Jewish patients--i.e., Jewish patients of Eastern/Northern European descent--with invasive ovarian cancer and in a measurable proportion (2%) of the general Ashkenazi Jewish population. However, uncertainty exists concerning the heritable basis of borderline ovarian tumors and whether these tumors represent an early form of ultimately invasive disease. To gain insight into these issues, we determined the rates of 185delAG-BRCA1 and 6174delT-BRCA2 mutations in patients with borderline ovarian tumors.
Analysis of 185delAG-BRCA1 and 6174delT-BRCA2 germline mutations was performed by use of a heteroduplex formation assay in samples from 46 consecutive patients with borderline ovarian tumors and 59 consecutive patients with invasive epithelial ovarian cancers. Forty-eight samples were also analyzed by restriction enzyme analysis for the presence of the 5382insC-BRCA1 mutation, a mutation detected in 2.2% of Ashkenazi Jewish patients with breast, but not ovarian, cancer.
One (2.2%) of the 46 patient with borderline tumors was identified as a carrier of the 185delAG-BRCA1 mutation, and no patients were found to carry the 6174delT-BRCA2 mutation. Nineteen (32%) of the 59 patients with invasive ovarian cancer were found to carry one of these two mutations; 17 carried 185delAG-BRCA1 and two carried 6174delT-BRCA2 (chi2 test with continuity correction, P = .00028). None of the patients analyzed for 5382insC-BRCA1 were found to carry the mutation. In one high-risk family that included 185delAG-BRCA1 carriers, a single patient with stage IIIc borderline ovarian tumor did not carry the mutation.
Invasive epithelial and borderline ovarian tumors appear to differ in their genetic predisposition and in the molecular mechanisms underlying their genesis.
已知BRCA1和BRCA2基因的种系突变与乳腺癌和上皮性卵巢癌风险增加相关。在相当比例（20%-60%）未经选择的阿什肯纳兹犹太患者（即东欧/北欧裔犹太患者）的浸润性卵巢癌中以及在可检测比例（2%）的阿什肯纳兹犹太普通人群中检测到了两种特定突变，即185delAG-BRCA1和6174delT-BRCA2。然而，关于交界性卵巢肿瘤的遗传基础以及这些肿瘤是否代表最终浸润性疾病的早期形式仍存在不确定性。为深入了解这些问题，我们测定了交界性卵巢肿瘤患者中185delAG-BRCA1和6174delT-BRCA2突变的发生率。
采用异源双链形成分析法对46例连续的交界性卵巢肿瘤患者和59例连续的浸润性上皮性卵巢癌患者的样本进行185delAG-BRCA1和6174delT-BRCA2种系突变分析。还对48个样本进行了限制性酶切分析，以检测5382insC-BRCA1突变的存在，该突变在2.2%的阿什肯纳兹犹太乳腺癌患者而非卵巢癌患者中检测到。
46例交界性肿瘤患者中有1例（2.2%）被鉴定为185delAG-BRCA1突变携带者，未发现携带6174delT-BRCA2突变的患者。59例浸润性卵巢癌患者中有19例（32%）被发现携带这两种突变之一；17例携带185delAG-BRCA1，2例携带6174delT-BRCA2（连续性校正卡方检验，P = 0.00028）。检测5382insC-BRCA1的患者均未发现携带该突变。在一个包括185delAG-BRCA1携带者的高危家族中，1例IIIc期交界性卵巢肿瘤患者未携带该突变。
浸润性上皮性和交界性卵巢肿瘤在遗传易感性及其发生的分子机制方面似乎存在差异。
