Höppener Diederik J, Verheul Sanne M L, Nierop Pieter M H, Buisman Florian E, Galjart Boris, Wilting Saskia M, Pugh Siân A, Richman Susan D, Balachandran Vinod P, Jarnagin William R, Kingham T Peter, Vermeulen Peter B, Shia Jinru, Quirke Philip, Bridgewater John A, Maughan Timothy S, Groot Koerkamp Bas, Grünhagen Dirk J, Verhoef Cornelis, Primrose John N, D'Angelica Michael I
Departments of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
Br J Cancer. 2025 Jul 23. doi: 10.1038/s41416-025-03103-4.
The histopathological growth patterns (HGPs) of colorectal cancer liver metastases broadly classify patients into two groups post-liver metastasectomy, with encapsulated HGP indicating a more favourable prognosis. The potential association between HGPs and specific mutations is poorly understood.
Using next-generation sequencing data of 461 resected patients (104 patients with encapsulated versus 357 patients with non-encapsulated HGP), 19 putative colorectal cancer driver genes, tumour mutational burden (TMB), and microsatellite instability (MSI) or POLE mediated hypermutation were compared.
Most putative drivers, including KRAS (q = 0.89), NRAS (q = 0.98),) and BRAF (q = 0.97)), were not associated with HGP. However, mutations in B2M and PTEN were associated with a encapsulated phenotype (7% vs. 0%, q = 0.001, and 9% vs. 2%, q = 0.02, respectively). TMB was higher in encapsulated patients (median 5.8 vs. 5.1 mutations per megabase, p = 0.009). Multivariable overall survival analysis corrected for genetic and patient factors confirmed that the encapsulated phenotype was an independent prognostic factor (adjusted hazard ratio, 0.60; 95% confidence interval: 0.36-0.99). Upon stratified analysis, all identified genetic associations were equivocal between the cohorts.
While an association between genetic drivers of adaptive immune responses seems probable and could explain a minority of encapsulated patients, these results primarily demonstrate that HGP phenotype is independent of the tumour genotype.
结直肠癌肝转移的组织病理学生长模式（HGPs）在肝转移切除术后大致将患者分为两组，包膜型HGPs提示预后更佳。HGPs与特定突变之间的潜在关联尚不清楚。
利用461例接受切除术患者的二代测序数据（104例包膜型患者与357例非包膜型患者），比较了19个假定的结直肠癌驱动基因、肿瘤突变负荷（TMB）以及微卫星不稳定性（MSI）或POLE介导的高突变情况。
大多数假定的驱动基因，包括KRAS（q = 0.89）、NRAS（q = 0.98）和BRAF（q = 0.97），均与HGPs无关。然而，B2M和PTEN的突变与包膜型表型相关（分别为7%对0%，q = 0.001；9%对2%，q = 0.02）。包膜型患者的TMB更高（中位数为每兆碱基5.8个突变对5.1个突变，p = 0.009）。经遗传和患者因素校正的多变量总生存分析证实，包膜型表型是一个独立的预后因素（调整后风险比为0.60；95%置信区间：0.36 - 0.99）。分层分析显示，所有已确定的遗传关联在各队列之间均不明确。
虽然适应性免疫反应的遗传驱动因素之间似乎存在关联，且可以解释少数包膜型患者的情况，但这些结果主要表明HGPs表型独立于肿瘤基因型。
