Genome-Derived Classification Signature for Ampullary Adenocarcinoma to Improve Clinical Cancer Care.
Genome-Derived Classification Signature for Ampullary Adenocarcinoma to Improve Clinical Cancer Care.
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DOI：
10.1158/1078-0432.ccr-21-1906
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发表时间：
2021-11-01
期刊：
影响因子：
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通讯作者：
Jarnagin WR
中科院分区：
文献类型：
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作者：
Chakraborty S;Ecker BL;Seier K;Aveson VG;Balachandran VP;Drebin JA;D'Angelica MI;Kingham TP;Sigel CS;Soares KC;Vakiani E;Wei AC;Chandwani R;Gonen M;Shen R;Jarnagin WR
壶腹腺癌的临床表现差异很大。靶向肿瘤测序可以更好地定义生物学上不同的亚型，以改善诊断和管理。隐藏基因组算法是一种多级元特征回归模型，在3，411名患者（1，001名胰腺癌，165名远端胆管腺癌，2，245名结直肠腺癌）的前瞻性测序队列中进行训练，随后应用于壶腹腺癌的靶向组DNA测序数据。基因组分类（即，结肠直肠对胰腺）与标准组织学分类（即，肠[INT] vs.胰胆[PB]）和临床结局。结直肠基因组亚型预测主要受APC和PIK3CA突变、肿瘤突变负荷和DNA错配修复（MMR）缺陷特征的影响。胰腺基因组亚型预测由KRAS基因改变决定，特别是KRAS G12D、KRAS G12R和KRAS G12V。远端胆管腺癌基因组亚型受MDM2基因拷贝数增加的影响最大。尽管免疫形态学亚型和基因组类别之间的一致性很高（73%），但两种组织学亚型内均存在显著的基因组异质性。与胰腺癌概率较高的患者相比，结直肠癌概率较高的基因组评分与较高的生存率相关。基因组分类器提供了对壶腹腺癌异质性的深入了解，并改善了分层，这取决于结直肠和胰腺基因组改变的比例。这种方法是可重复的可用的分子检测和避免主观的组织学解释。
The clinical behavior of ampullary adenocarcinoma varies widely. Targeted tumor sequencing may better define biologically distinct subtypes to improve diagnosis and management. The hidden genome algorithm, a multilevel meta-feature regression model, was trained on a prospectively sequenced cohort of 3,411 patients (1,001 pancreatic adenocarcinoma, 165 distal bile duct adenocarcinoma, 2,245 colorectal adenocarcinoma) and subsequently applied to targeted panel DNA sequencing data from ampullary adenocarcinomas. Genomic classification (i.e., colorectal vs. pancreatic) was correlated with standard histological classification (i.e., intestinal [INT] vs. pancreatobiliary [PB]) and clinical outcome. Colorectal genomic subtype prediction was primarily influenced by mutations in APC and PIK3CA, tumor mutational burden, and DNA mismatch repair (MMR) deficiency signature. Pancreatic genomic subtype prediction was dictated by KRAS gene alterations, particularly KRAS G12D, KRAS G12R, and KRAS G12V. Distal bile duct adenocarcinoma genomic subtype was most influenced by copy number gains in the MDM2 gene. Despite high (73%) concordance between immunomorphologic subtype and genomic category, there was significant genomic heterogeneity within both histologic subtypes. Genomic scores with higher colorectal probability were associated with greater survival compared to those with a higher pancreatic probability. The genomic classifier provides insight into the heterogeneity of ampullary adenocarcinoma and improves stratification, which is dictated by the proportion of colorectal and pancreatic genomic alterations. This approach is reproducible with available molecular testing and obviates subjective histologic interpretation.