Campbell Family Institute for Breast Cancer Research, Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
Clin Cancer Res. 2012 Nov 15;18(22):6199-207. doi: 10.1158/1078-0432.CCR-12-2155. Epub 2012 Sep 11.
Women who have inherited germline mutations of BRCA1/BRCA2 are at increased risk of developing high-grade serous carcinoma, and many of these cancers arise in the distal fimbriated end of the fallopian tube. We have previously shown that the fallopian tube epithelia of BRCA1 mutation carriers (FTE-BRCA) have altered signaling pathways compared to nonmutation carriers. In this study, we sought to determine whether these differences result in a proliferative advantage to the epithelia in this high-risk patient population and to investigate whether the postovulation environment of the FTE-BRCA compared to FTE from nonmutation carriers experiences a differential abundance of immune cells.
Immunohistochemistry for Ki67, CD3, CD8, CD20, and CD68 was performed on histologically normal tubal epithelium (ampulla, n = 83), fimbria (n = 18) with known ovarian cycle status and germline mutation status and for Ki67 on fimbrial epithelium from women (n = 144) with and without BRCA1 or BRCA2 mutations who underwent risk-reducing salpingo-oophorectomy (RRSO). Serous tubal intraepithelial carcinomas (STIC) with concomitant cancer (n = 15) were also analyzed for presence of immune infiltrates. All slides were digitized and analyzed using automated image analysis software.
There was no significant difference in the proliferative index in histologically normal FTE between BRCA1/BRCA2 and non-BRCA, in 144 fimbriae and 83 ampullae. The FTE-BRCA1 epithelia did not exhibit a differential presence of lymphocytes or macrophages, however more macrophages were present in the luteal phase compared to the follicular phase epithelia. In STICs macrophages were more abundant than lymphocytes with an incremental increase noted with disease progression.
BRCA1/2 mutation carriers exhibited no significant increase in proliferation in the fallopian tube epithelial cells either in the ampulla or fimbriated ends of the tube. Rather, a significant proliferative increase was defined in the cases determined to be in the follicular, or proliferative, preovulatory phase of the ovarian cycle. Finally, we also show an incremental increase in leukocytes invading the STICs and HGSC, implicating a possible role of the leukocytes early in the progression or inhibition of tumor formation, which is independent of ovarian cycle status.
携带 BRCA1/BRCA2 种系突变的女性发生高级别浆液性癌的风险增加，而这些癌症中的许多起源于输卵管远端的伞端。我们之前已经表明，与非突变携带者相比，BRCA1 突变携带者的输卵管上皮（FTE-BRCA）具有改变的信号通路。在这项研究中，我们试图确定这些差异是否导致高危患者群体的上皮细胞增殖优势，并研究与非突变携带者的 FTE 相比，FTE-BRCA 中是否在排卵后环境中经历了免疫细胞的差异丰度。
对组织学正常的输卵管上皮（壶腹，n=83）、已知卵巢周期状态和种系突变状态的输卵管伞端（n=18）以及接受预防性输卵管卵巢切除术（RRSO）的 BRCA1 或 BRCA2 突变的女性的输卵管伞端上皮（n=144）进行 Ki67、CD3、CD8、CD20 和 CD68 的免疫组织化学染色。同时伴有癌症的输卵管浆液性上皮内癌（STIC）（n=15）也进行了免疫浸润分析。所有幻灯片均使用自动图像分析软件进行数字化和分析。
在 BRCA1/BRCA2 和非 BRCA 的 144 个伞端和 83 个壶腹中，组织学正常的 FTE 之间的增殖指数没有显著差异。FTE-BRCA1 上皮细胞中没有出现淋巴细胞或巨噬细胞的差异存在，然而，黄体期的上皮细胞中存在更多的巨噬细胞。在 STIC 中，巨噬细胞比淋巴细胞更为丰富，并且随着疾病的进展，数量逐渐增加。
BRCA1/2 突变携带者的输卵管上皮细胞在输卵管的壶腹或伞端均未表现出明显的增殖增加。相反，在被确定处于卵巢周期的卵泡期或增殖期的预排卵期的情况下，明显的增殖增加。最后，我们还显示了浸润 STIC 和 HGSC 的白细胞的递增增加，提示白细胞可能在肿瘤形成的早期进展或抑制中起作用，这与卵巢周期状态无关。
