3'-非翻译区 KRAS 变异与三阴性乳腺癌：病例对照与遗传分析。
A 3'-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis.
机构信息
Department of Therapeutic Radiology, Yale University, New Haven, CT 06880, USA.
出版信息
Lancet Oncol. 2011 Apr;12(4):377-86. doi: 10.1016/S1470-2045(11)70044-4. Epub 2011 Mar 22.
BACKGROUND
We previously identified a functional variant in a let-7 microRNA (miRNA) complementary site in the 3'-untranslated region of the KRAS oncogene (rs61764370) which is associated with cancer. We aimed to investigate the association of this KRAS variant with breast cancer and tumour biology.
METHODS
We assessed frequency distributions of the KRAS variant in 415 patients with histologically confirmed breast cancer and 457 controls from Connecticut, USA (study group 1) and association of this variant with breast-cancer subtypes in 690 Irish women with known oestrogen receptor (ER), progesterone receptor (PR), and HER2 statuses, and 360 controls (study group 2). We pooled data for study groups 1 and 2 with a cohort of 140 women with triple-negative breast cancer and 113 controls to assess the association of the KRAS variant with triple-negative breast cancer risk, and genome-wide mRNA and specific miRNA expression in patients with triple-negative breast cancer.
FINDINGS
Although frequency distributions of the KRAS variant in study group 1 did not differ between all genotyped individuals, eight (33%) of 24 premenopausal women with ER/PR-negative cancer had the KRAS variant, compared with 27 (13%) of 201 premenopausal controls (p=0.015). In study group 2, the KRAS variant was significantly enriched in women with triple-negative breast cancer (19 [21%] of 90 cases) compared with 64 (13%) of 478 for luminal A, 13 (15%) of 87 for luminal B, and two (6%) of 35 for HER2-positive subgroups (p=0.044). Multivariate analysis in the pooled study groups showed that the KRAS variant was associated with triple-negative breast cancer in premenopausal women (odds ratio 2.307, 95% CI 1.261-4.219, p=0.0067). Gene-expression analysis of triple-negative breast-cancer tumours suggested that KRAS-variant positive tumours have significantly altered gene expression, and are enriched for the luminal progenitor and BRCA1 deficiency signatures. miRNA analysis suggested reduced levels of let-7 miRNA species in KRAS-variant tumours.
INTERPRETATION
The KRAS variant might be a genetic marker for development of triple-negative breast cancer in premenopausal women, and altered gene and miRNA expression signatures should enable molecular and biological stratification of patients with this subgroup of breast cancer.
FUNDING
US National Institutes of Health.
背景
我们之前在 KRAS 致癌基因（rs61764370）的 3'-非翻译区的一个 let-7 微 RNA（miRNA）互补位点中发现了一个功能性变异，该变异与癌症有关。我们旨在研究这种 KRAS 变异与乳腺癌和肿瘤生物学之间的关系。
方法
我们评估了 415 名经组织学证实的乳腺癌患者和 457 名来自美国康涅狄格州的对照者中 KRAS 变异的频率分布（研究组 1），并评估了该变异与 690 名已知雌激素受体（ER）、孕激素受体（PR）和 HER2 状态的爱尔兰女性乳腺癌亚型之间的关系，以及 360 名对照者（研究组 2）。我们将研究组 1 和 2 的数据与 140 名三阴性乳腺癌患者和 113 名对照者的数据进行了合并，以评估 KRAS 变异与三阴性乳腺癌风险之间的关系，以及三阴性乳腺癌患者的全基因组 mRNA 和特定 miRNA 表达。
结果
尽管研究组 1 中所有基因分型个体的 KRAS 变异频率分布没有差异，但 24 名 ER/PR 阴性癌症的绝经前女性中有 8 名（33%）存在 KRAS 变异，而 201 名绝经前对照者中有 27 名（13%）（p=0.015）。在研究组 2 中，KRAS 变异在三阴性乳腺癌患者中明显富集（90 例中有 19 例[21%]），而在 luminal A 组中为 64 例（13%），在 luminal B 组中为 13 例（15%），在 HER2 阳性亚组中为 2 例（6%）（p=0.044）。合并研究组的多变量分析显示，KRAS 变异与绝经前女性的三阴性乳腺癌有关（优势比 2.307，95%置信区间 1.261-4.219，p=0.0067）。三阴性乳腺癌肿瘤的基因表达分析表明，KRAS 变异阳性肿瘤的基因表达明显改变，并且富含 luminal 祖细胞和 BRCA1 缺陷特征。miRNA 分析表明，KRAS 变异肿瘤中的 let-7 miRNA 水平降低。
结论
KRAS 变异可能是绝经前女性三阴性乳腺癌发生的遗传标志物，改变的基因和 miRNA 表达特征应能实现该亚组乳腺癌患者的分子和生物学分层。
资助
美国国立卫生研究院。
Zotero 插件