Timms Kirsten M, Abkevich Victor, Hughes Elisha, Neff Chris, Reid Julia, Morris Brian, Kalva Saritha, Potter Jennifer, Tran Thanh V, Chen Jian, Iliev Diana, Sangale Zaina, Tikishvili Eliso, Perry Michael, Zharkikh Andrey, Gutin Alexander, Lanchbury Jerry S
Myriad Genetics Inc., 320 Wakara Way, 84108, Salt Lake City, UT, USA.
Breast Cancer Res. 2014 Dec 5;16(6):475. doi: 10.1186/s13058-014-0475-x.
Homologous recombination (HR) DNA repair is of clinical relevance in breast cancer. Three DNA-based homologous recombination deficiency (HRD) scores (HRD-loss of heterozygosity score (LOH), HRD-telomeric allelic imbalance score (TAI), and HRD-large-scale state transition score (LST)) have been developed that are highly correlated with defects in BRCA1/2, and are associated with response to platinum therapy in triple negative breast and ovarian cancer. This study examines the frequency of BRCA1/2 defects among different breast cancer subtypes, and the ability of the HRD scores to identify breast tumors with defects in the homologous recombination DNA repair pathway.
215 breast tumors representing all ER/HER2 subtypes were obtained from commercial vendors. Next-generation sequencing based assays were used to generate genome wide SNP profiles, BRCA1/2 mutation screening, and BRCA1 promoter methylation data.
BRCA1/2 deleterious mutations were observed in all breast cancer subtypes. BRCA1 promoter methylation was observed almost exclusively in triple negative breast cancer. BRCA1/2 deficient tumors were identified with BRCA1/2 mutations, or BRCA1 promoter methylation, and loss of the second allele of the affected gene. All three HRD scores were highly associated with BRCA1/2 deficiency (HRD-LOH: P = 1.3 × 10(-17); HRD-TAI: P = 1.5 × 10(-19); HRD-LST: P = 3.5 × 10(-18)). A combined score (HRD-mean) was calculated using the arithmetic mean of the three scores. In multivariable analyses the HRD-mean score captured significant BRCA1/2 deficiency information not captured by the three individual scores, or by clinical variables (P values for HRD-Mean adjusted for HRD-LOH: P = 1.4 × 10(-8); HRD-TAI: P = 2.9 × 10(-7); HRD-LST: P = 2.8 × 10(-8); clinical variables: P = 1.2 × 10(-16)).
The HRD scores showed strong correlation with BRCA1/2 deficiency regardless of breast cancer subtype. The frequency of elevated scores suggests that a significant proportion of all breast tumor subtypes may carry defects in the homologous recombination DNA repair pathway. The HRD scores can be combined to produce a more robust predictor of HRD. The combination of a robust score, and the FFPE compatible assay described in this study, may facilitate use of agents targeting homologous recombination DNA repair in the clinical setting.
同源重组（HR）DNA修复在乳腺癌中具有临床相关性。已经开发出三种基于DNA的同源重组缺陷（HRD）评分（HRD-杂合性缺失评分（LOH）、HRD-端粒等位基因不平衡评分（TAI）和HRD-大规模状态转换评分（LST）），它们与BRCA1/2缺陷高度相关，并与三阴性乳腺癌和卵巢癌对铂类治疗的反应相关。本研究调查了不同乳腺癌亚型中BRCA1/2缺陷的频率，以及HRD评分识别同源重组DNA修复途径存在缺陷的乳腺肿瘤的能力。
从商业供应商处获取了代表所有ER/HER2亚型的215例乳腺肿瘤。使用基于二代测序的检测方法来生成全基因组SNP图谱、BRCA1/2突变筛查以及BRCA1启动子甲基化数据。
在所有乳腺癌亚型中均观察到BRCA1/2有害突变。BRCA1启动子甲基化几乎仅在三阴性乳腺癌中观察到。通过BRCA1/2突变、BRCA1启动子甲基化以及受影响基因的第二个等位基因缺失来识别BRCA1/2缺陷肿瘤。所有三种HRD评分均与BRCA1/2缺陷高度相关（HRD-LOH：P = 1.3×10⁻¹⁷；HRD-TAI：P = 1.5×10⁻¹⁹；HRD-LST：P = 3.5×10⁻¹⁸）。使用这三个评分的算术平均值计算出一个综合评分（HRD-均值）。在多变量分析中，HRD-均值评分捕捉到了单个评分或临床变量未捕捉到的显著BRCA1/2缺陷信息（针对HRD-LOH调整后的HRD-均值P值：P = 1.4×10⁻⁸；HRD-TAI：P = 2.9×10⁻⁷；HRD-LST：P = 2.8×10⁻⁸；临床变量：P = 1.2×10⁻¹⁶）。
无论乳腺癌亚型如何，HRD评分均与BRCA1/2缺陷密切相关。评分升高的频率表明，所有乳腺肿瘤亚型中有很大一部分可能在同源重组DNA修复途径中存在缺陷。HRD评分可以合并以产生更强大的HRD预测指标。一个强大的评分与本研究中描述的FFPE兼容检测方法相结合，可能有助于在临床环境中使用针对同源重组DNA修复的药物。
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