Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, 70-115 Szczecin, Poland.
Breast Cancer Res Treat. 2012 Apr;132(3):937-45. doi: 10.1007/s10549-011-1635-7. Epub 2011 Jun 24.
Germline mutations in BRCA1 were already linked to basal-like subtype of immunophenotypic molecular classification of breast cancer (BC). However, it is not known whether mutations in other BC susceptibility genes are associated with molecular subtypes of this cancer. We tested the hypothesis that distinct mutations in another BC susceptibility gene involved in DNA repair, i.e., CHEK2 may be associated with particular immunophenotypic molecular subtypes of this cancer. Two groups of patients: 1255 with BCs and 5496 healthy controls were genotyped for four CHEK2 mutations (I157T and three truncating mutations: 1100delC, IVS2 + 1G > A, del5395). BCs were tested by immunohistochemistry on tissue microarrays for ER, PR, HER-2, EGFR, and CK5/6 and were assigned to appropriate subtypes of immunophenotypic molecular classification. There was a significant association between CHEK2 mutations and the immunophenotypic molecular classification (P = 0.004). CHEK2-associated cancers were predominantly luminal (108/117 = 92.3%). CHEK2-I157T variant was associated with the luminal A subtype (P = 0.01), whereas CHEK2-truncating mutations were associated with the luminal B subtype (P = 0.005). Comparing the prevalence of CHEK2 mutations in BC with controls revealed that carriers of an I157T variant had OR of 1.80 for luminal A subtype and carriers of truncating mutations had OR of 6.26 for luminal B subtype of BC. To our knowledge, this is the first study showing that specific mutations in the same susceptibility gene are associated with different immunophenotypic molecular subtypes of BC. This association represents independent evidence supporting the biological significance of immunophenotypic molecular classification of BC.
BRCA1 种系突变已与乳腺癌（BC）免疫表型分子分类的基底样亚型相关。然而，其他 BC 易感性基因的突变是否与这种癌症的分子亚型相关尚不清楚。我们检验了这样一种假设，即另一个参与 DNA 修复的 BC 易感性基因 CHEK2 的不同突变可能与这种癌症的特定免疫表型分子亚型相关。我们对两组患者进行了基因分型：1255 例 BC 患者和 5496 例健康对照，检测了 CHEK2 的四个突变（I157T 和三个截断突变：1100delC、IVS2 + 1G > A、del5395）。BC 患者的组织微阵列进行了 ER、PR、HER-2、EGFR 和 CK5/6 的免疫组化检测，并被分配到适当的免疫表型分子分类亚型。CHEK2 突变与免疫表型分子分类之间存在显著相关性（P = 0.004）。CHEK2 相关的癌症主要为管腔型（108/117 = 92.3%）。CHEK2-I157T 变体与 luminal A 亚型相关（P = 0.01），而 CHEK2 截断突变与 luminal B 亚型相关（P = 0.005）。与对照组相比，BC 中 CHEK2 突变的发生率显示，I157T 变体携带者 luminal A 亚型的 OR 为 1.80，截断突变携带者 luminal B 亚型的 OR 为 6.26。据我们所知，这是第一项表明同一易感性基因的特定突变与 BC 的不同免疫表型分子亚型相关的研究。这种关联代表了支持 BC 免疫表型分子分类生物学意义的独立证据。
