Genomic Variations and Immune-related Features in Undifferentiated Carcinoma with Osteoclast-like Giant Cells of the Pancreas: a single center retrospective cohort study

Background: Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas (UCOGCP) was a rare malignancy. Literature on UCOGCP was limited, especially about mutation landscape and immune-related features.Methods: In the present study, the patients with UCOGCP admitted to West China Hospital of Sichuan University from 2010 and 2020 were retrospectively enrolled and followed until August 30, 2022. Whole exome sequencing (WES) and PD-L1 expression of tumor tissue from the 6 UCOGCP patients were performed to collect genomic variation and immune-related features of patients with UCOGCP.Results: We identified 11 (0.2%) patients with UCOGCP in the entire cohort of 5730 patients with pancreatic cancer (PC). 9 UCOGCPs were finally included in the analysis. In our cohorts, the median overall survival (mOS) was 39.8 months for UCOGCPs. Notably, compared with unresected patients (mOS, 9.1 months), the mOS of UCOGCPs who underwent surgical resection was dramatically improved (95.7 months). Molecular analysis in 6 samples revealed the most common gene mutations included KRAS (50%, 3/6) and TP53 (50%, 3/6) mutations. Two samples harbored a missense mutation at the same site of the LRP1 gene (33%). The median level of TMB was 0.75 mutations/Mb (range: 0 to 1.53 mutations/Mb). 100% of patients (6/6) were microsatellite stability (MSS). Three of 6 patients showed positive PD-L1 expression (tumor proportion score > 10%). Our study demonstrated a tendency that over-expression of PD-L1 was conversely related to survival time.Conclusions: This study demonstrated that the prognosis for resected UCOGCP was favorable in comparison to resected conventional pancreatic ductal adenocarcinoma (PDAC). Surgical resection still was the key to treat this disease. UCOGCP was similar to conventional PDAC at the molecular level, sharing somatic mutations in the most commonly mutated genes of PDAC. In addition, the mutations in LRP1 gene might be the potential driver of UCOGCP and be associated with poor prognosis. UCOGCP was characterized by low TMB, largely in MSS status and higher PD-L1 positive expression rates and extend. The expression of PD-L1 in UCOGCP indicated poor prognosis but such patients might benefit from immunotherapy.

背景：胰腺伴破骨细胞样巨细胞未分化癌（UCOGCP）是一种罕见的恶性肿瘤。目前关于UCOGCP的研究文献较为匮乏，尤其是在突变谱与免疫相关特征方面。方法：本研究回顾性纳入2010年至2020年于四川大学华西医院就诊的UCOGCP患者，并随访至2022年8月30日。对6例UCOGCP患者的肿瘤组织进行全外显子组测序（WES）及PD-L1表达检测，以获取UCOGCP患者的基因组变异与免疫相关特征数据。结果：在5730例胰腺癌（PC）患者的全部队列中，我们共筛选出11例（0.2%）UCOGCP患者，最终有9例UCOGCP病例纳入本次分析。本队列中UCOGCP患者的中位总生存期（mOS）为39.8个月。值得注意的是，与未接受手术切除的患者（mOS：9.1个月）相比，接受手术切除的UCOGCP患者的中位总生存期显著延长（95.7个月）。对6例样本的分子分析显示，最常见的基因突变包括KRAS突变（50%，3/6）与TP53突变（50%，3/6）。有2例样本存在LRP1基因同一位点的错义突变（33%）。肿瘤突变负荷（TMB）的中位值为0.75突变/Mb（范围：0~1.53突变/Mb）。所有患者（6/6，100%）均为微卫星稳定（MSS）。6例患者中有3例PD-L1表达阳性（肿瘤比例评分＞10%）。本研究发现，PD-L1过表达与患者生存时间呈负相关趋势。结论：本研究证实，与接受手术切除的常规胰腺导管腺癌（PDAC）患者相比，手术切除后的UCOGCP患者预后更佳。手术切除仍是该病治疗的核心手段。在分子层面，UCOGCP与常规PDAC具有相似性，二者共享胰腺癌最常见突变基因的体细胞突变。此外，LRP1基因突变可能是UCOGCP的潜在驱动突变，并与不良预后相关。UCOGCP的特征为肿瘤突变负荷较低、以微卫星稳定状态为主，且PD-L1阳性表达率较高、表达范围更广。UCOGCP患者的PD-L1表达提示不良预后，但此类患者或可从免疫治疗中获益。