醫學新聞：基因研究將乳房癌分成四種新的亞型

這四種新的亞型為：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.

相關的老文章：2012年4月18日，Nature雜誌發表了乳腺癌的一張“新地圖”，確認了10個不同的疾病亞型，是基於基因活性進行確認的，這張新地圖將會徹底改變乳腺癌的診斷和治療。該結果來自於全球最大的乳腺癌基因分析課題。

　　這項研究意義非凡，著名的乳腺癌專家Martine Piccart教授講到，目前乳腺癌的分類分型過於簡單，使得我們在選擇病人的治療上無法達到最優。我一點都不感到驚訝，乳腺癌不止4種分型，而至少有10種亞型，我相信這項發現會讓我們更好的治療患者，盡管這可能還需要10年。

　　英國和加拿大研究者分析了2000個腫瘤樣本，來自於5~10年前診斷為乳腺癌的婦女。他們整合了腫瘤樣本拷貝數、基因表達和長期臨床結局的數據。得出結論，基於共同的與生存相關的遺傳特征，這些樣本可以至少分成10種不同的亞型。

　　接下來就是要在臨床試驗中加以證實，最終目的是對每種腫瘤類型的精確的“基因指紋”進行靶向治療。該研究結果為醫生診斷乳腺癌類型，選擇起作用的藥物類型鋪平了道路，在用藥上將會更加精準。這項裏程碑式的研究將徹底改變我們診治乳腺癌的方法。

　　目前的病理亞型

　　目前，乳腺癌被病理學家分為4種亞型，主要基於雌激素受體（ER）和HER2，前者陽性表明對激素治療有反應，後者陽性表明對赫賽汀治療有反應。

　　到目前為止，乳腺癌中最常見（70%）的病理類型是ER+/HER2-，7.5%是ER+/HER2+，7.5是ER-/HER2+，另外一種就是所謂的三陰性乳腺癌，侵襲強，不能從靶向治療中獲益，目前還是使用化療。

　　然而，在歸類到ER+/HER2-的乳腺癌中，還存在巨大的異質性，某些患者比其他患者有更好的預後。研究人員發現，10種新確認的疾病類型中有7種在這個類別中。在預後上有廣泛的差異，15年中，最好的結果是80%生存率，最差的是40%生存率，我們從這個最常見的亞組中發現了更多的分歧，這是非常重要的，因為我們一直在尋求該組患者中更好的標誌物。

　　研究者還發現了幾個新的基因，例如激酶和磷酸酶，是新藥開發的非常有吸引力的目標。

原文閱讀：

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.