医学新闻：基因研究将乳房癌分成四种新的亚型

这四种新的亚型为：1）luminal A；2）luminal B； 3）basal-like；and 4）HER2-enriched (HER2E)。

HER2-enriched: This subtype includes many, but not all, HER2-positive tumors, or ones that express large amounts of the HER2 protein. Tends to respond to drugs that target the HER2 protein.

Luminal A: Estrogen-positive; tends to be less aggressive.

Luminal B: Estrogen-positive; tends to be more aggressive.

Basal-like: Includes many, but not all, triple-negative breast cancers, and tends to be aggressive. A smaller percentage in this subtype may express HER2 and/or estrogen.

The luminal A subtype harboured the most significantly mutated genes, with the most frequent being PIK3CA (45%), followed by MAP3K1, GATA3, TP53, CDH1 and MAP2K4. Twelve per cent of luminal A tumours contained likely inactivating mutations in MAP3K1 and MAP2K4, which represent two contiguous steps in the p38–JNK1 stress kinase pathway。

Luminal B cancers exhibited a diversity of significantly mutated genes, with TP53 and PIK3CA (29% each) being the most frequent.

Basal-like cancers have TP53 mutations occurred in 80% of cases and the majority of the luminal significantly mutated gene repertoire, except PIK3CA (9%), were absent or near absent. 

HER2E subtype has frequent HER2 amplification (80%), had a hybrid pattern with a high frequency of TP53 (72%) and PIK3CA (39%) mutations and a much lower frequency of other significantly mutated genes including PIK3R1 (4%).

The new finding offers hints that one type of breast cancer might be vulnerable to drugs that already work against ovarian cancer.

The study, published online Sunday by the journal Nature, is the latest example of research into the biological details of tumors, rather than focusing primarily on where cancer arises in the body.

The hope is that such research can reveal cancer's genetic weaknesses for better drug targeting.

"With this study, we're one giant step closer to understanding the genetic origins of the four major subtypes of breast cancer," Dr. Matthew Ellis of the Washington University School of Medicine said in a statement. He is a co-leader of the research.

"Now we can investigate which drugs work best for patients based on the genetic profiles of their tumors," he said.

The researchers analyzed DNA of breast cancer tumors from 825 patients, looking for abnormalities. Altogether, they reported, breast cancers appear to fall into four main classes when viewed in this way.

One class showed similarities to ovarian cancers, suggesting it may be driven by similar biological developments.

"It's clear they are genetically more similar to ovarian tumors than to other breast cancers," Ellis said. "Whether they can be treated the same way is an intriguing possibility that needs to be explored."

The report is the latest from the Cancer Genome Atlas, a federally funded project that has produced similar analyses for brain, colorectal, lung, and ovarian cancers.

相关的老文章：2012年4月18日，Nature杂志发表了乳腺癌的一张“新地图”，确认了10个不同的疾病亚型，是基于基因活性进行确认的，这张新地图将会彻底改变乳腺癌的诊断和治疗。该结果来自于全球最大的乳腺癌基因分析课题。

　　这项研究意义非凡，著名的乳腺癌专家Martine Piccart教授讲到，目前乳腺癌的分类分型过于简单，使得我们在选择病人的治疗上无法达到最优。我一点都不感到惊讶，乳腺癌不止4种分型，而至少有10种亚型，我相信这项发现会让我们更好的治疗患者，尽管这可能还需要10年。

　　英国和加拿大研究者分析了2000个肿瘤样本，来自于5~10年前诊断为乳腺癌的妇女。他们整合了肿瘤样本拷贝数、基因表达和长期临床结局的数据。得出结论，基于共同的与生存相关的遗传特征，这些样本可以至少分成10种不同的亚型。

　　接下来就是要在临床试验中加以证实，最终目的是对每种肿瘤类型的精确的“基因指纹”进行靶向治疗。该研究结果为医生诊断乳腺癌类型，选择起作用的药物类型铺平了道路，在用药上将会更加精准。这项里程碑式的研究将彻底改变我们诊治乳腺癌的方法。

　　目前的病理亚型

　　目前，乳腺癌被病理学家分为4种亚型，主要基于雌激素受体（ER）和HER2，前者阳性表明对激素治疗有反应，后者阳性表明对赫赛汀治疗有反应。

　　到目前为止，乳腺癌中最常见（70%）的病理类型是ER+/HER2-，7.5%是ER+/HER2+，7.5是ER-/HER2+，另外一种就是所谓的三阴性乳腺癌，侵袭强，不能从靶向治疗中获益，目前还是使用化疗。

　　然而，在归类到ER+/HER2-的乳腺癌中，还存在巨大的异质性，某些患者比其他患者有更好的预后。研究人员发现，10种新确认的疾病类型中有7种在这个类别中。在预后上有广泛的差异，15年中，最好的结果是80%生存率，最差的是40%生存率，我们从这个最常见的亚组中发现了更多的分歧，这是非常重要的，因为我们一直在寻求该组患者中更好的标志物。

　　研究者还发现了几个新的基因，例如激酶和磷酸酶，是新药开发的非常有吸引力的目标。

原文阅读：

The genomic and transcriptomic architecture of 2，000 breast tumours reveals novel subgroups

Christina Curtis, Sohrab P. Shah, Suet-Feung Chin, Gulisa Turashvili, Oscar M. Rueda, Mark J. Dunning, Doug Speed, Andy G. Lynch, Shamith Samarajiwa, Yinyin Yuan, Stefan Grf, Gavin Ha, Gholamreza Haffari,Ali Bashashati, Roslin Russel Steven McKinney, METABRIC Group, Anita Langerd, Andrew Green, Elena Provenzano,8 Gordon Wishart, Sarah Pinder, Peter Watson, Florian Markowetz,Leigh Murphy

　　The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.