雌激素受体阳性乳腺癌的“罪魁祸首”

　　2016年8月29日，英国《自然·遗传学》在线发表加拿大玛格丽特公主癌症中心、多伦多大学、安大略癌症研究所、美国达特茅斯医学院、诺里斯·柯顿癌症中心、斯坦福大学医学院、麻省理工学院（MIT）的研究报告，发现在雌激素受体阳性乳腺癌发展过程中，积累在肿瘤中的基因外突变，是触发这种疾病的主要罪魁祸首。

　　该研究集中关注乳腺癌最常见的类型——雌激素受体阳性乳腺癌，通过表观遗传学方法分析基因外获得性突变，发现功能性调控元件可以被改变，而影响基因表达，以促进乳腺癌生长。

　　该研究分析患者肿瘤积累DNA序列变化，与雌激素受体阳性乳腺癌细胞表观遗传特性有关。

　　如果将基因看作人类基因组的“光源”，该研究表明驱动突变不仅会打开“灯”，还直接改变作为功能性调控成分的“光开关”和“调光器”。

　　该研究为基因组开发带来了机会，不仅在基因中，而且也在其他功能性调控元件发现驱动突变，以增强确定最佳生物标志物的能力，并描绘每个肿瘤的基本生物学特征，以帮助推进乳腺癌患者的个体化治疗。

Nat Genet. 2016 Aug 29. [Epub ahead of print]

Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer.

Bailey SD, Desai K, Kron KJ, Mazrooei P, Sinnott-Armstrong NA, Treloar AE, Dowar M, Thu KL, Cescon DW, Silvester J, Yang SY, Wu X, Pezo RC, Haibe-Kains B, Mak TW, Bedard PL, Pugh TJ, Sallari RC, Lupien M.

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada; Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire, USA; Stanford University School of Medicine, Stanford, California, USA; Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk-associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.

PMID: 27571262

DOI: 10.1038/ng.3650