`Analysis of neo-antigens and immune profiles of Asian breast cancer patients, focusing on common germline deletion of APOBEC3B cytosine deaminase
`分析亚洲乳腺癌患者的新抗原和免疫特征,重点关注 APOBEC3B 胞嘧啶脱氨酶的常见种系缺失
基本信息
- 批准号:MR/P012442/1
- 负责人:
- 金额:$ 25.17万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2017
- 资助国家:英国
- 起止时间:2017 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Breast cancer is the most common cancer among women, and in Asia, breast cancer incidence is increasing at 3% per annum because of increasing "westernization" and urbanization, along with changes in lifestyle factors. Much effort to catalogue the genomic alterations in common types of cancers including breast cancer, but this has mainly been done in women of European descent. Molecular profiling of breast cancer in multi-ethnic Asian populations has been limited in part because of cost and unavailability of large collections of good quality, clinically annotated tumour samples. The goal of understanding the genomic basis of Asian breast cancers can now be realized because newer DNA sequencing technologies provide high-throughput and accurate data at a significantly reduced cost. We have decided to focus on breast cancers arising in germline carriers of APOBEC3B (A3B) deletion, which is three times more common in Asians compared to Caucasians. The APOBEC ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like") family of proteins are evolutionarily conserved cytosine deaminases associated with intrinsic mutations in response to viral and bacterial infection. Recently, germline A3B deletions were reported to be associated with increased risk to breast cancer, and breast cancers that have a hypermutator phenotype and activated immune signature. However, in part because germline mutations are less common in Caucasian populations and the majority of large sequencing projects have thus far been conducted in Caucasian sample collections, there remains limited information about A3B in breast cancers, particularly in Asian breast cancer samples. Tumour-infiltrating immune cells play a role in immunesurveillance and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 antibodies have been shown to elicit remarkable response in treatment of melanoma, non-small-cell lung cancer, renal-cell carcinoma, and other cancers. However, only a small fraction of patients benefit and it appears that cancers with higher mutation load are more likely benefit due to immune activation and consequently increased tumour-infiltrating immune cells. Indeed, colorectal patients with high mutation burden because of mismatch repair deficiency showed better immune-related objective response rate and progression-free survival, suggesting that high somatic mutation burden may be a predictive potential biomarker to immune checkpoint inhibitors. To date, there has been limited data of tumour response to immune checkpoint therapy in breast cancer. The majority of breast cancers in women of European descent are post menopausal breast cancer which is more likely to be positive for estrogen receptor and have a lower mutational load. However, for a subset of breast cancers, for example, those with triple negative breast cancers, with BRCA1 or BRCA2 germline alterations, and with A3B germline mutations, there is higher mutational load. Notably, the mutational load in Asian breast cancer samples, where A3B germline mutations are 3 times more common, has not yet been systematically tested in Asian women.Since 2012, we have established hospital-based cohort of breast cancer samples collected in fresh frozen format and all samples are associated with in depth risk factor information, sequencing for a comprehensive panel of 30 breast cancer predisposition genes, and A3B germline status analysis, thus providing a unique opportunity for this collaboration. In this project, we propose to conduct a systematic analysis of the mutational profile and immune response in a cohort of women with either wild-type, 1 copy deletion or 2 copy deletion of A3B and determine germline A3B status is associated with anti-tumour response. We believe that this work will lead to a better understanding of a common germline alteration in Asian women and may lay the grounds for future studies on immunotherapy in Asian breast cancer patients.
乳腺癌是女性中最常见的癌症,在亚洲,由于“西方化”和城市化的增加,以及生活方式因素的改变,乳腺癌发病率以每年3%的速度增长。对包括乳腺癌在内的常见癌症类型的基因组变化进行了大量的编目,但这主要是在欧洲血统的女性中完成的。亚洲多种族人群乳腺癌的分子谱分析一直受到限制,部分原因是成本和无法获得大量高质量、临床注释的肿瘤样本。了解亚洲乳腺癌基因组基础的目标现在可以实现,因为新的DNA测序技术以显著降低的成本提供了高通量和准确的数据。我们决定将重点放在APOBEC3B (A3B)缺失的生殖系携带者中发生的乳腺癌上,这种缺失在亚洲人中的发生率是高加索人的三倍。APOBEC(“载脂蛋白B mRNA编辑酶,催化多肽样”)蛋白家族是进化上保守的胞嘧啶脱氨酶,与病毒和细菌感染的内在突变相关。最近,据报道,种系A3B缺失与乳腺癌风险增加有关,乳腺癌具有超突变表型和激活的免疫特征。然而,部分原因是种系突变在白种人人群中不太常见,而且迄今为止大多数大型测序项目都是在白种人样本中进行的,因此关于乳腺癌中A3B的信息仍然有限,特别是在亚洲乳腺癌样本中。肿瘤浸润性免疫细胞在免疫监视和免疫检查点抑制剂中发挥作用,如抗pd -1和抗ctla -4抗体,已被证明在黑色素瘤、非小细胞肺癌、肾细胞癌和其他癌症的治疗中引起显着的反应。然而,只有一小部分患者受益,突变负荷较高的癌症似乎更有可能受益,因为免疫激活,从而增加肿瘤浸润性免疫细胞。事实上,由于错配修复缺陷导致的高突变负担的结直肠癌患者表现出更好的免疫相关客观反应率和无进展生存率,这表明高体细胞突变负担可能是免疫检查点抑制剂的预测潜在生物标志物。迄今为止,乳腺癌中肿瘤对免疫检查点治疗的反应数据有限。大多数欧洲裔女性的乳腺癌是绝经后的乳腺癌雌激素受体更有可能呈阳性突变负荷更低。然而,对于乳腺癌的一个子集,例如,三阴性乳腺癌,BRCA1或BRCA2种系改变,以及A3B种系突变,有更高的突变负荷。值得注意的是,亚洲乳腺癌样本中的突变负荷,其中A3B种系突变的发生率是亚洲女性的3倍,尚未在亚洲女性中进行系统测试。自2012年以来,我们已经建立了以医院为基础的以新鲜冷冻形式收集的乳腺癌样本队列,所有样本都与深度风险因素信息相关,对30个乳腺癌易感基因进行了全面测序,并对A3B种系状态进行了分析,从而为此次合作提供了独特的机会。在这个项目中,我们建议对A3B野生型、1拷贝缺失或2拷贝缺失的女性队列进行系统的突变谱和免疫反应分析,并确定种系A3B状态与抗肿瘤反应相关。我们相信这项工作将有助于更好地了解亚洲女性常见的种系改变,并可能为未来亚洲乳腺癌患者的免疫治疗研究奠定基础。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Lymphocyte density determined by computational pathology validated as a predictor of response to neoadjuvant chemotherapy in breast cancer: secondary analysis of the ARTemis trial.
- DOI:10.1093/annonc/mdx266
- 发表时间:2017-08-01
- 期刊:
- 影响因子:0
- 作者:Ali HR;Dariush A;Thomas J;Provenzano E;Dunn J;Hiller L;Vallier AL;Abraham J;Piper T;Bartlett JMS;Cameron DA;Hayward L;Brenton JD;Pharoah PDP;Irwin MJ;Walton NA;Earl HM;Caldas C
- 通讯作者:Caldas C
DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation.
- DOI:10.1038/s41467-021-25661-w
- 发表时间:2021-09-13
- 期刊:
- 影响因子:16.6
- 作者:Batra RN;Lifshitz A;Vidakovic AT;Chin SF;Sati-Batra A;Sammut SJ;Provenzano E;Ali HR;Dariush A;Bruna A;Murphy L;Purushotham A;Ellis I;Green A;Garrett-Bakelman FE;Mason C;Melnick A;Aparicio SAJR;Rueda OM;Tanay A;Caldas C
- 通讯作者:Caldas C
Lymphocyte density determined by computational pathology validated as a predictor of response to neoadjuvant chemotherapy in breast cancer: secondary analysis of the ARTemis trial
通过计算病理学确定的淋巴细胞密度被验证为乳腺癌新辅助化疗反应的预测因子:ARTemis 试验的二次分析
- DOI:10.17863/cam.10082
- 发表时间:2017
- 期刊:
- 影响因子:0
- 作者:Ali H
- 通讯作者:Ali H
Intersect-then-combine approach: improving the performance of somatic variant calling in whole exome sequencing data using multiple aligners and callers.
- DOI:10.1186/s13073-017-0425-1
- 发表时间:2017-04-18
- 期刊:
- 影响因子:12.3
- 作者:Callari M;Sammut SJ;De Mattos-Arruda L;Bruna A;Rueda OM;Chin SF;Caldas C
- 通讯作者:Caldas C
Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care.
- DOI:10.1200/po.22.00245
- 发表时间:2022-12
- 期刊:
- 影响因子:4.6
- 作者:
- 通讯作者:
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Carlos Caldas其他文献
Frequent Somatic Deletion of the 13ql2.3 Locus Encompassing <em>BRCA2</em> in Chronic Lymphocytic Leukemia
- DOI:
10.1182/blood.v88.5.1568.1568 - 发表时间:
1996-09-01 - 期刊:
- 影响因子:
- 作者:
Jose A. Garcia-Marco;Carlos Caldas;Cathy M. Price;Leanne M. Wiedemann;Alan Ashworth;Daniel Catovsky - 通讯作者:
Daniel Catovsky
Cancer Core Europe: A European cancer research alliance realizing a research infrastructure with critical mass and programmatic approach to cure cancer in the 21st century
- DOI:
10.1016/j.ejca.2018.08.023 - 发表时间:
2018-11-01 - 期刊:
- 影响因子:
- 作者:
Fabien Calvo;Giovanni Apolone;Michael Baumann;Carlos Caldas;Julio E. Celis;Franceso de Lorenzo;Ingemar Ernberg;Ulrik Ringborg;John Rowell;Josep Tabernero;Emile Voest;Alexander Eggermont - 通讯作者:
Alexander Eggermont
Cancer sequencing unravels clonal evolution
癌症测序揭示了克隆进化。
- DOI:
10.1038/nbt.2213 - 发表时间:
2012-05-07 - 期刊:
- 影响因子:41.700
- 作者:
Carlos Caldas - 通讯作者:
Carlos Caldas
Fitness and transcriptional plasticity of human breast cancer single-cell-derived clones
人类乳腺癌单细胞衍生克隆的适应性和转录可塑性
- DOI:
10.1016/j.celrep.2025.115699 - 发表时间:
2025-05-27 - 期刊:
- 影响因子:6.900
- 作者:
Long V. Nguyen;Yaniv Eyal-Lubling;Daniel Guerrero-Romero;Sarah Kronheim;Suet-Feung Chin;Raquel Manzano Garcia;Stephen-John Sammut;Giulia Lerda;Allan J.W. Lui;Helen A. Bardwell;Wendy Greenwood;Hee Jin Shin;Riccardo Masina;Katarzyna Kania;Alejandra Bruna;Elham Esmaeilishirazifard;Emily A. Kolyvas;Samuel Aparicio;Oscar M. Rueda;Carlos Caldas - 通讯作者:
Carlos Caldas
A pooled analysis evaluating prognostic significance of Residual Cancer Burden in invasive lobular breast cancer
一项评估浸润性小叶乳腺癌中残留癌负荷预后意义的荟萃分析
- DOI:
10.1038/s41523-025-00720-3 - 发表时间:
2025-02-13 - 期刊:
- 影响因子:7.600
- 作者:
Rita A. Mukhtar;Soumya Gottipati;Christina Yau;Sara López-Tarruella;Helena Earl;Larry Hayward;Louise Hiller;Marie Osdoit;Marieke van der Noordaa;Diane de Croze;Anne-Sophie Hamy;Marick Laé;Fabien Reyal;Gabe S. Sonke;Tessa G. Steenbruggen;Maartje van Seijen;Jelle Wesseling;Miguel Martín;Maria del Monte-Millán;Judy C. Boughey;Matthew P. Goetz;Tanya Hoskin;Vicente Valero;Stephen B. Edge;Jean E. Abraham;John M. S. Bartlett;Carlos Caldas;Janet Dunn;Elena Provenzano;Stephen-John Sammut;Jeremy S. Thomas;Ashley Graham;Peter Hall;Lorna Mackintosh;Fang Fan;Andrew K. Godwin;Kelsey Schwensen;Priyanka Sharma;Angela M. DeMichele;Kimberly Cole;Lajos Pusztai;Mi-Ok Kim;Laura J van ’t Veer;David Cameron;Laura J. Esserman;W. Fraser Symmans - 通讯作者:
W. Fraser Symmans
Carlos Caldas的其他文献
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{{ truncateString('Carlos Caldas', 18)}}的其他基金
Realt-Time Spatial Information Acquisition and Use for Infrastructure Construction and Maintenance
实时空间信息获取和用于基础设施建设和维护
- 批准号:
0409326 - 财政年份:2004
- 资助金额:
$ 25.17万 - 项目类别:
Standard Grant
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一种用于任意序列DNA和RNA高效编辑的HpSGN-neo系统
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