PO.MD01.02 · 分子诊断与数据

AACR GENIE 数据库中皮肤附属器癌的基因组全景：对精准癌症医学的意义

The genomic landscape of skin adnexal carcinomas in the AACR GENIE database: Implications for precision cancer medicine

编号 4104 展板 9 时间 4/21 09:00–12:00 区域 Section 1 主讲 Valbert Filho, No Degree

分会场 AACR Project GENIE: Genomic Characterization

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作者与单位 Authors & Affiliations

Valbert Oliveira Costa Filho¹, Mariana Macambira Noronha¹, Pedro Robson Costa Passos¹, Carlos Diego Holanda Lopes², Giuseppe G. F. Leite³, Carlos Wagner de Souza Wanderley⁴, Sam D. Saibil⁵, Danielle Calheiros Campelo Maia¹, Erick F. Saldanha²

¹Universidade Federal do Ceara, Fortaleza, Brazil,²Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada,³Division of Infectious Diseases, Department of Medicine, Escola Paulista de Medicina Universidade Federal de Sao Paulo, São Paulo, Brazil,⁴Brigham and Women's Hospital, Harvard Medical School, Boston, MA,⁵Department of Medicine, University of Toronto, Toronto, ON, Canada, Toronto, ON, Canada

摘要 Abstract

中文摘要

皮肤附属器癌（SAC）是罕见且异质性的恶性肿瘤。这组肿瘤由皮肤附属器（例如毛囊和皮脂腺）分化而来，在分子和临床上与角质形成细胞癌截然不同。复发或转移性 SAC 是侵袭性肿瘤，生存结局差，且可用的治疗选择有限。在此，我们利用 AACR GENIE 数据库来揭示 SAC 的基因组全景。根据世界卫生组织分类被归类为 SAC 的样本的基因组数据从 AACR GENIE 1.8 数据集中选取，并使用 OncoKB TM 数据库进行注释。肿瘤突变负荷（TMB）值由 AACR 团队提供，分类定义为低（<2 mut/Mb）、中（2 至 16 mut/Mb）和高（>16 mut/Mb）。生成了突变特征并与 COMISC 数据库进行匹配。共检索到 224 例样本，包括原发（73.7%，n=165）和转移（26.3%，n=59）肿瘤。临床人口统计学分析显示 53.6%（n=120）为女性，种族分布为白人（73.2%；n=164）、亚裔（10.3%；n=23）、黑人（5.4%；n=12）和未指定（11.1%；n=25）。乳腺外 Paget 病是最常见的亚型（48.7%；109 例），其次是具有大汗腺/小汗腺分化（32.6%；n=73）、皮脂腺分化（17.4%；n=39）和毛囊分化（1.3%；n=3）的肿瘤。每例样本的中位突变数为 4（IQR 2-3）。最频繁突变的基因是 TP53（45%）、PIK3CA（20%）、KMT2C（17%）、ERBB2（17%）和 NOTCH1（12%）。主要改变的通路涉及 RTK-RAS（54.9%）、TP53（48.7%）和 PI3K（37.1%）。最频繁的拷贝数缺失见于 CDKN2A（11.8%）和 CDKN2B（10.5%）。主要的拷贝数增益见于 ERBB2（8.7%）和 MYC（8.1%）。由 OncoKB TM 注释的最频繁可操作突变发生于 PIK3CA（1 级；17%）、ERBB2（1 级；12%）、CDKN2A（4 级，4.9%）、PTCH1（3A 级，4.5%）和 ARID1A（4 级，4%）。在 2.2% 的患者中检测到可操作的 BRAF 突变（0.4% 为 1 级，1.8% 为 2 级），而 KRAS 1 级突变在 3.6% 的患者中观察到。中位 TMB 为 2.7 mut/Mb（IQR 0.85-6.83），38.8%（n=87）样本为低 TMB，48.6%（n=109）为中 TMB，12.5%（n=28）为高 TMB。匹配到三种 COSMIC 突变特征：SBS2（APOBEC 胞苷脱氨酶家族的活性）、SBS6（DNA 错配修复缺陷）和 SBS7b（紫外线暴露），分别在 37.4%、36.9% 和 25.7% 的肿瘤中占主导。我们的研究分析了迄今报道的最大的 SAC 队列，并识别出一部分具有高 TMB 和可操作基因组改变（包括按 OncoKB 的 1 级改变）的患者。这些发现突出了基因组谱分析在 SAC 中的相关性，可为临床决策提供依据、实现临床试验匹配，并改善对这些罕见恶性肿瘤的生物学理解。

查看英文原文 English abstract

Skin adnexal carcinomas (SAC) are rare and heterogeneous malignancies. These group of tumors differentiate from skin appendageal, such as hair follicles and sebaceous glands, and are molecularly and clinically distinct from keratinocyte carcinomas. Recurrent or metastatic SACs are aggressive tumors with poor survival outcomes, and limited available therapeutic options. Here we leveraged the AACR GENIE database to uncover the genomic landscape of SAC. Genomic data from samples classified as SAC according to the World Health Organization classification were selected from the AACR GENIE 1.8 dataset and annotated using the OncoKB TM database. Tumor mutation burden (TMB) values were provided by the AACR team, with classification defined as low (<2 mut/Mb), intermediate (2 to 16 mut/Mb), and high (>16 mut/Mb). Mutational signatures were generated and matched to the COMISC database. A total of 224 samples were retrieved, including primary (73.7%, n=165) and metastatic (26.3%, n=59) tumors. Clinicodemographic analysis revealed 53.6% (n=120) female and identified race distribution as white (73.2%; n=164), Asian (10.3%; n=23), black (5.4%; n=12) and non-specified (11.1%; n=25). Extramammary Paget disease was the most common subtype (48.7%; 109), followed by tumors with apocrine/eccrine (32.6%; n=73), sebaceous (17.4%; n=39), and follicular differentiation (1.3%; n=3). The median number of mutations per sample was 4 (IQR 2-3). The most frequently mutated genes were TP53 (45%), PIK3CA (20%), KMT2C (17%), ERBB2 (17%), and NOTCH1 (12%). The main altered pathways involved RTK-RAS (54.9%), TP53 (48.7%) and PI3K (37.1%). The most frequent copy number losses were in CDKN2A (11.8%) and CDKN2B (10.5%). The main copy number gains were observed in ERBB2 (8.7%) and MYC (8.1%). The most frequent actionable mutations annotated by OncoKB TM occurred in PIK3CA (Level 1; 17%), ERBB2 (Level 1; 12%), CDKN2A (Level 4, 4.9%), PTCH1 (Level 3A, 4.5%), and ARID1A (Level 4, 4%). Actionable BRAF mutations were detected in 2.2% of patients (0.4% Level 1 and 1.8% Level 2), whereas KRAS Level 1 mutations were observed in 3.6% of patients. The median TMB was 2.7 mut/Mb (IQR 0.85-6.83), 38.8% (n=87) samples had low TMB, 48.6% (n=109) had intermediate TMB, and 12.5% (n=28) had high TMB. Three COSMIC mutational signatures were matched: SBS2 (activity of APOBEC family of cytidine deaminases), SBS6 (defective DNA mismatch repair), and SBS7b (ultraviolet exposure), dominating 37.4%, 36.9%, and 25.7% of tumors, respectively. Our study profiled the largest cohort of SACs reported to date and identified a subset of patients with high TMB and actionable genomic alterations, including Level 1 alterations per OncoKB. These findings highlight the relevance of genomic profiling in SACs to inform clinical decision making, enable clinical trial matching, and improve the biological understanding of these rare malignancies.

利益披露 Disclosure

V. O. C. Filho, None.. M. M. Noronha, None.. P. R. C. Passos, None.. C. D. H. Lopes, None.. G. G. F. Leite, None.. C. W. D. Wanderley, None.. S. D. Saibil, None.. D. C. C. Maia, None.. E. F. Saldanha, None.

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