Cancer Res.:BRCA1基因突变乳腺癌中的RB1基因异常

6月15日，Cancer Research杂志在线报道了BRCA1基因突变携带者的乳腺癌研究的最新进展。生殖细胞系BRCA1基因突变携带者的乳腺癌常显示基底样分子亚型的典型特征。然而，BRCA1功能失调导致哪些基因反复突变尚不清楚。

在这项研究中，研究者利用基因表达谱对577例乳腺肿瘤进行分子亚型分类，其中包括72例乳腺肿瘤BRCA1/2突变基因携带者。以RB1位点为重点,研究者使用覆盖RB1基因的自定义设计高密度寡聚微阵列,分析了33 例BRCA1基因突变，36 例BRCA2基因突变和48 例non-BRCA1/2-mutated的乳腺肿瘤患者。

他们发现在基底样亚型和BRCA1基因突变的乳腺肿瘤和管腔B亚型以及BRCA2基因突变的乳腺肿瘤之间存在强烈关联。在BRCA1基因突变携带者乳腺肿瘤患者和散发BRCA1基因启动子甲基化乳腺肿瘤患者中，RB1被确定为一个基因组破坏的主要目标。但这很少发生在其他类型乳腺癌。

研究者发现，在33％的BRCA1基因突变乳腺肿瘤，36％的BRCA1基因启动子甲基化的基底细胞样肿瘤，13％的非BRCA1基因缺陷的基底细胞样肿瘤，3％的BRCA2基因突变肿瘤中，RB1的存在纯合性缺失，基因内断裂，或微缺失。

总之，广泛基因破坏导致的RB1失活经常发生在BRCA1基因相关的遗传性乳腺癌基因的破坏和BRCA1基因甲基化的散发基底样乳腺癌，但很少在BRCA2基因遗传性乳腺癌和非BRCA1基因缺陷的散发性乳腺癌。总之，研究结果表明在基底样亚型乳腺癌中的遗传异质性取决于BRCA1基因状态。

doi:10.1016/j.cell.2011.10.017
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The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer 

Gran Jnsson1,2,§, Johan Staaf1,2,§, Johan Vallon-Christersson1,2,§, Markus Ringnér1,2, Sofia K Gruvberger-Saal1,2, Lao H Saal1,2, Karolina Holm1,2, Cecilia Hegardt1,2, Adalgeir Arason3,4, Rainer Fagerholm5, Camilla Persson1,2, Dorthe Grabau6, Ellinor Johnsson1,2, Kristina L?vgren1, Linda Magnusson7, P?ivi Heikkil?8, Bjarni A Agnarsson3,4, Oskar T Johannsson3, Per Malmstr?m1,9, M?rten Fern?1, H?kan Olsson1,

 Niklas Loman1,9, Heli Nevanlinna5, Rosa B Barkardottir3,4, ?ke Borg1,2Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we utilized gene expression profiling to molecularly subtype 577 breast tumors, including 72 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter-methylation, but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1 deficient basal-like tumors, and 3% of BRCA2-mutated tumo rs. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1-related hereditary breast cancer and BRCA1-methylated sporadic ba sal-like breast cancer, but  rarely in BRCA2-hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings demonstrate the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1-status.