Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Breast Cancer Res. 2010;12(6):R95. doi: 10.1186/bcr2776. Epub 2010 Nov 16.
The majority of breast cancers that occur in BRCA1 mutation carriers (BRCA1 carriers) are estrogen receptor-negative (ER-). Therefore, it has been suggested that ER negativity is intrinsic to BRCA1 cancers and reflects the cell of origin of these tumors. However, approximately 20% of breast cancers that develop in BRCA1 carriers are ER-positive (ER+); these cancers are more likely to develop as BRCA1 carriers age, suggesting that they may be incidental and unrelated to BRCA1 deficiency. The purpose of this study was to compare the prevalence of loss of heterozygosity due to loss of wild type (wt) BRCA1 in ER+ and ER- breast cancers that have occurred in BRCA1 carriers and to determine whether age at diagnosis or any pathologic features or biomarkers predict for loss of wt BRCA1 in these breast cancers.
Relative amounts of mutated and wt BRCA1 DNA were measured by quantitative polymerase chain reaction performed on laser capture microdissected cancer cells from 42 ER+ and 35 ER- invasive breast cancers that developed in BRCA1 carriers. BRCA1 gene methylation was determined on all cancers in which sufficient DNA was available. Immunostains for cytokeratins (CK) 5/6, 14, 8 and 18, epidermal growth factor receptor and p53 were performed on paraffin sections from tissue microarrays containing these cancers.
Loss of wt BRCA1 was equally frequent in ER+ and ER- BRCA1-associated cancers (81.0% vs 88.6%, respectively; P = 0.53). One of nine cancers tested that retained wt BRCA1 demonstrated BRCA1 gene methylation. Age at diagnosis was not significantly different between first invasive ER+ BRCA1 breast cancers with and without loss of wt BRCA1 (mean age 45.2 years vs 50.1 years, respectively; P = 0.51). ER+ BRCA1 cancers that retained wt BRCA1 were significantly more likely than those that lost wt BRCA1 to have a low mitotic rate (odds ratio (OR), 5.16; 95% CI, 1.91 to ∞). BRCA1 cancers with loss of wt BRCA1 were more likely to express basal cytokeratins CK 5/6 or 14 (OR 4.7; 95% CI, 1.85 to ∞).
We found no difference in the prevalence of loss of wt BRCA1 between ER+ and ER- invasive BRCA1-associated breast cancers. Our findings suggest that many of the newer therapies for BRCA1 breast cancers designed to exploit the BRCA1 deficiency in these cancers may also be effective in ER+ cancers that develop in this population.
发生在 BRCA1 突变携带者（BRCA1 携带者）中的大多数乳腺癌为雌激素受体阴性（ER-）。因此，有人认为 ER 阴性是 BRCA1 癌症的固有特征，并反映了这些肿瘤的起源细胞。然而，大约 20%在 BRCA1 携带者中发生的乳腺癌为雌激素受体阳性（ER+）；这些癌症随着 BRCA1 携带者年龄的增长而更有可能发生，这表明它们可能是偶然的，与 BRCA1 缺乏无关。本研究的目的是比较 BRCA1 携带者中发生的 ER+和 ER-乳腺癌中由于野生型（wt）BRCA1 缺失而导致的杂合性丢失的发生率，并确定诊断时的年龄或任何病理特征或生物标志物是否可预测这些乳腺癌中 wt BRCA1 的缺失。
通过对 BRCA1 携带者中发生的 42 例 ER+和 35 例 ER-浸润性乳腺癌的激光捕获显微切割癌细胞进行定量聚合酶链反应，测量突变和 wt BRCA1 DNA 的相对量。对所有有足够 DNA 的癌症进行 BRCA1 基因甲基化检测。对包含这些癌症的组织微阵列的石蜡切片进行细胞角蛋白（CK）5/6、14、8 和 18、表皮生长因子受体和 p53 的免疫染色。
ER+和 ER-BRCA1 相关癌症中 wt BRCA1 的缺失频率相等（分别为 81.0%和 88.6%；P=0.53）。在检测的 9 例保留 wt BRCA1 的癌症中，有 1 例显示 BRCA1 基因甲基化。诊断时的年龄在保留 wt BRCA1 的 ER+BRCA1 乳腺癌和无 wt BRCA1 缺失的 ER+BRCA1 乳腺癌之间无显著差异（平均年龄分别为 45.2 岁和 50.1 岁；P=0.51）。保留 wt BRCA1 的 ER+BRCA1 乳腺癌比丢失 wt BRCA1 的 ER+BRCA1 乳腺癌更有可能具有低有丝分裂率（比值比（OR），5.16；95%置信区间，1.91 至 ∞）。丢失 wt BRCA1 的 BRCA1 癌症更可能表达基底细胞角蛋白 CK5/6 或 14（OR 4.7；95%置信区间，1.85 至 ∞）。
我们未发现 ER+和 ER-侵袭性 BRCA1 相关乳腺癌中 wt BRCA1 缺失的发生率存在差异。我们的研究结果表明，许多针对 BRCA1 乳腺癌设计的旨在利用这些癌症中 BRCA1 缺陷的新型疗法，可能也对该人群中发生的 ER+乳腺癌有效。
