對(duì)致命癌癥的特征進(jìn)行分子水平詳細(xì)解析，是認(rèn)識(shí)癌癥耐藥和免疫逃逸機(jī)制的先決條件。
2019年5月28日，美國(guó)《細(xì)胞》旗下《細(xì)胞報(bào)告》發(fā)表英國(guó)劍橋大學(xué)、英國(guó)國(guó)家健康研究院劍橋生物醫(yī)學(xué)研究中心、惠康基金會(huì)桑格研究所、英國(guó)醫(yī)學(xué)研究委員會(huì)劍橋干細(xì)胞研究所、英國(guó)癌癥研究基金會(huì)劍橋癌癥中心、西班牙腫瘤生物醫(yī)學(xué)研究網(wǎng)絡(luò)中心、巴塞羅那自治大學(xué)瓦爾德希伯倫醫(yī)院、馬德里大學(xué)拉蒙卡哈爾醫(yī)院、加泰羅尼亞高級(jí)研究院、以色列魏茨曼科學(xué)研究所、美國(guó)鳳凰城基因組學(xué)轉(zhuǎn)化研究所無(wú)創(chuàng)診斷中心、梅奧醫(yī)學(xué)中心、哈佛大學(xué)麻省理工學(xué)院布羅德研究所、哈佛大學(xué)麻省總醫(yī)院的研究報(bào)告，深入解析了致命轉(zhuǎn)移性乳腺癌的基因組特征和免疫特征。
該研究對(duì)10例轉(zhuǎn)移性乳腺癌耐藥患者尸體多部位轉(zhuǎn)移癌進(jìn)行多平臺(tái)廣泛分析。根據(jù)基因組學(xué)、轉(zhuǎn)錄組學(xué)、免疫學(xué)綜合分析，發(fā)現(xiàn)轉(zhuǎn)移癌以克隆群落的形式不斷繁衍、增殖、播散、分化，其新抗原特征可被預(yù)測(cè)，并且其人類白細(xì)胞抗原等位基因不斷由雜合狀態(tài)變成純合狀態(tài)。此外，該研究進(jìn)一步發(fā)現(xiàn)腫瘤微環(huán)境可變，并且通過(guò)T淋巴細(xì)胞受體庫(kù)分析發(fā)現(xiàn)，適應(yīng)性（獲得性、后天性）免疫應(yīng)答似乎與轉(zhuǎn)移癌基因組共同分化。
因此，該研究結(jié)果表明，致命轉(zhuǎn)移性乳腺癌患者的轉(zhuǎn)移癌具有共同的基因組來(lái)源，其譜系分化非常有限，不同轉(zhuǎn)移癌的腫瘤免疫微環(huán)境并不一致，不同轉(zhuǎn)移癌的譜系分化與腫瘤浸潤(rùn)淋巴細(xì)胞受體分化相關(guān)，故有必要進(jìn)一步開展致命癌癥基因組分析。
Cell Rep. 2019 May 28;27(9):2690-2708.e10.
The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer.
Leticia De Mattos-Arruda, Stephen-John Sammut, Edith M. Ross, Rachael Bashford-Rogers, Erez Greenstein, Havell Markus, Sandro Morganella, Yvonne Teng, Yosef Maruvka, Bernard Pereira, Oscar M. Rueda, Suet-Feung Chin, Tania Contente-Cuomo, Regina Mayor, Alexandra Arias, H. Raza Ali, Wei Cope, Daniel Tiezzi, Aliakbar Dariush, Tauanne Dias Amarante, Dan Reshef, Nikaoly Ciriaco, Elena Martinez-Saez, Vicente Peg, Santiago Ramon y Cajal, Javier Cortes, George Vassiliou, Gad Getz, Serena Nik-Zainal, Muhammed Murtaza, Nir Friedman, Florian Markowetz, Joan Seoane, Carlos Caldas.
University of Cambridge, Cambridge, UK; NIHR Cambridge Biomedical Research Centre, Cambridge, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Wellcome Trust/MRC Cambridge Stem Cell Institute, Cambridge, UK; Cancer Research UK Cambridge Cancer Centre, Cambridge, UK; Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain; Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain; Vall d'Hebron University Hospital, Barcelona, Spain; Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Ramon y Cajal Hospital, Madrid, Spain; Institució Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain; Weizmann Institute of Science, Rehovot, Israel; Center for Noninvasive Diagnostics, Translational Genomics Research Institute, Phoenix, AZ, USA; Mayo Clinic Center for Individualized Medicine, Scottsdale, AZ, USA; The Broad Institute, Cambridge, MA, USA; Massachusetts General Hospital Cancer Center, Charlestown, MA, USA.
HIGHLIGHTS
Genomic and transcriptomic landscapes for 10 lethal breast cancers
Within a patient, metastases group in limited clades with shared genomic ancestry
Tumor immune microenvironments across metastases are not uniform
Phylogenetic trees are correlated with TIL-TCR trees across metastases
The detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer.
KEYWORDS: breast cancer; metastases; stem mutations; clade mutations; private mutations; genomic landscapes; immune landscapes; metastatic phylogenies; immunoediting; TCR repertoire
DOI: 10.1016/j.celrep.2019.04.098
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