Low-density Lipoprotein Receptor-related Protein 1B Research Articles

LDL Receptor-Related Protein 1B Polymorphisms Associated with Increased Risk of Lymph Node Metastasis in Oral Cancer Group with Diabetes Mellitus.

Oral cancer ranks fourth among malignancies among Taiwanese men and is the eighth most common cancer among men worldwide in terms of general diagnosis. The purpose of the current study was to investigate how low-density lipoprotein receptor-related protein 1B (LDL receptor related protein 1B; LRP1B) gene polymorphisms affect oral squamous cell carcinoma (OSCC) risk and progression in individuals with diabetes mellitus (DM). Three LRP1B single-nucleotide polymorphisms (SNPs), including rs10496915, rs431809, and rs6742944, were evaluated in 311 OSCC cases and 300 controls. Between the case and control groups, we found no evidence of a significant correlation between the risk of OSCC and any of the three specific SNPs. Nevertheless, in evaluating the clinicopathological criteria, individuals with DM who possess a minimum of one minor allele of rs10496915 (AC + CC; p = 0.046) were significantly associated with tumor size compared with those with homozygous major alleles (AA). Similarly, compared to genotypes homologous for the main allele (GG), rs6742944 genotypes (GA + AA; p = 0.010) were more likely to develop lymph node metastases. The tongue and the rs6742944 genotypes (GA + AA) exhibited higher rates of advanced clinical stages (p = 0.024) and lymph node metastases (p = 0.007) when compared to homozygous alleles (GG). LRP1B genetic polymorphisms appear to be prognostic and diagnostic markers for OSCC and DM, as well as contributing to genetic profiling research for personalized medicine.

Abstract 3005: Low-density lipoprotein receptor-related protein 1B (LRP1B) depletion promotes tumorigenicity by modulating fibroblasts in the tumor microenvironment in esophageal squamous cell carcinoma

Abstract Background: Esophageal squamous cell carcinoma (ESCC) is widespread worldwide with a poor survival rate. Tumor cells shedding from tumor tissues traveling to other organs through the blood circulatory system are called circulating tumor cells (CTCs). The CTCs in the blood of ESCC patients were enriched and then subjected to CTC mutational profiling by target sequencing. Our results suggested that CTC mutations in low-density lipoprotein receptor-related protein 1B (LRP1B) may have a potential prognostic role for ESCC. LRP1B belongs to the low-density receptor (LDLR) family with diverse roles in cellular functions and development, but the function of LRP1B in ESCC remains unclear. Therefore, this study aims to do a functional characterization of LRP1B. Methods: The CRISPR cas9 system was used to functionally knock down the candidate gene in ESCC cell lines with the highest endogenous level of LRP1B. The in vitro cell proliferation rate and viability were measured by MTT assay, colony formation assay, and wound healing assay. The in vivo tumorigenicity assay was performed to evaluate the tumor suppressive effect by subcutaneous injection. To examine the clinical relevance of LRP1B, we also performed immunohistochemistry (IHC) in tumor tissue microarray (TMA). Results: The reduction or loss of LRP1B mRNA was demonstrated in 60% of a panel of 15 ESCC cell lines. The depletion of LRP1B did not influence cell proliferation, cell clonogenic ability, or cell migration in ECSS cell lines. However, LRP1B depletion significantly promoted the growth of tumors in mouse xenograft models. Therefore, we hypothesize that LRP1B may be involved in modulating the tumor microenvironment (TME) by impacting various stromal components leading to an immuno-suppressive TME. We utilized RT-qPCR to investigate markers of various stromal components and observed that fibroblast markers (acta2, pdgfrb, and vimentin) had significantly higher expression levels after LRP1B downregulation in ESCC cell-derived mouse xenografts. The higher level of fibroblast cells was then verified by IHC staining. Further molecular mechanistic studies are underway and are expected to provide novel therapeutic insights by targeting the LRP1B genes. The LRP1B ESCC TMA data analysis is underway and statistical analysis will be presented. Conclusions: LRP1B plays a tumor-suppressive role in ESCC by modulating the tumor-associated fibroblasts in the TME. Acknowledgements: TBRS grant T12-701/17R and HMRF grant 05160926 to MLL Citation Format: KaiYan Xu, Josephine Mun-yee KO, Valen Zhuo you Yu, Maria Li LUNG. Low-density lipoprotein receptor-related protein 1B (LRP1B) depletion promotes tumorigenicity by modulating fibroblasts in the tumor microenvironment in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3005.

Prognostic Implications of LRP1B and Its Relationship with the Tumor-Infiltrating Immune Cells in Gastric Cancer.

Recent studies have shown that low-density lipoprotein receptor-related protein 1b (LRP1B), as a potential tumor suppressor, is implicated in the response to immunotherapy. The frequency of LRP1B mutation gene is high in many cancers, but its role in gastric cancer (GC) has not been determined. The prognostic value of LRP1B mutation in a cohort containing 100 patients having received radical gastrectomy for stage II-III GC was explored. By analyzing the data of LRP1B mRNA, the risk score of differentially expressed genes (DEGs) between LRP1B mutation-type and wild-type was constructed based on the TCGA-STAD cohort. The infiltration of tumor immune cells was evaluated by the CYBERSORT algorithm and verified by immunohistochemistry. LRP1B gene mutation was an independent risk factor for disease-free survival (DFS) in GC patients (HR = 2.57, 95% CI: 1.28-5.14, p = 0.008). The Kaplan-Meier curve demonstrated a shorter survival time in high-risk patients stratified according to risk score (p < 0.0001). CYBERSORT analysis showed that the DEGs were mainly concentrated in CD4+ T cells and macrophages. TIMER analysis suggested that LRP1B expression was associated with the infiltration of CD4+ T cells and macrophages. Immunohistochemistry demonstrated that LRP1B was expressed in the tumor cells (TCs) and immune cells in 16/89 and 26/89 of the cohort, respectively. LRP1B-positive TCs were associated with higher levels of CD4+ T cells, CD8+ T cells, and CD86/CD163 (p < 0.05). Multivariate analysis showed that LRP1B-positive TCs represented an independent protective factor of DFS in GC patients (HR = 0.43, 95% CI: 0.10-0.93, p = 0.042). LRP1B has a high prognostic value in GC. LRP1B may stimulate tumor immune cell infiltration to provide GC patients with survival benefits.

LRP1B—a prognostic marker in tubo-ovarian high-grade serous carcinoma

Low-density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a member of the LDLreceptor family and has often been discussed as a tumor suppressor gene, as its down-regulation is correlated with a poor prognosis in multiple carcinoma entities. Due to the high metastasis rate into the fatty peritoneal cavity and current research findings showing a dysregulation of lipid metabolism in tubo-ovarian high-grade serous carcinoma (HGSC), we questioned the prognostic impact of the LRP1B protein expression. We examined a well-characterized large cohort of 571 patients with primary HGSC and analyzed the LRP1B protein expression via immunohistochemical staining (both in tumor and stroma cells separately), performed precise bioimage analysis with QuPath, and calculated the prognostic impact using SPSS. Our results demonstrate that LRP1B functions as a significant prognostic marker for overall survival (OS) and progression-free survival (PFS) in HGSC on the protein level. High cytoplasmic expression of LRP1B in tumor, stroma, and combined tumor and stroma cells has a significantly positive association with a mean prolongation of the OS by 42 months (P=.005), 29 months (P=.005), and 25 months (P=.001), respectively. Additionally, the mean PFS was 18 months longer in tumor (P=.002), 19 months in stroma (P=.004), and 19 months in both cell types combined (P=.01). Our results remained significant in multivariate analysis. We envision LRP1B as a potential prognostic tool that could help us understand the functional role of lipid metabolism in advanced HGSC, especially regarding liposomal medications.

Utilizing Proteomic Approaches to Uncover the Neuroprotective Effects of ACE Inhibitors: Implications for Alzheimer's Disease Treatment.

Two types of angiotensin-converting enzyme (ACE) inhibitors, lisinopril and benazepril HCl, were tested in neuroblastoma cells and found to upregulate low-density lipoprotein-receptor-related protein 1B (LRP1B) and 14-3-3 protein zeta/delta. Additionally, benazepril HCl was found to increase the expression of calreticulin. The upregulation of these proteins by ACE inhibitors may contribute to the amelioration of cognitive deficits in Alzheimer's disease/dementia, as well as the clinically observed deceleration of functional decline in Alzheimer's patients. This discovery suggests that the supplementation of ACE inhibitors may promote neuronal cell survival independently of their antihypertensive effect. Overall, these findings indicate that ACE inhibitors may be a promising avenue for developing effective treatments for Alzheimer's disease.

Whole-Exome Sequencing Revealed the Mutational Profiles of Primary Central Nervous System Lymphoma.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive type of extranodal non-Hodgkin lymphoma, of which approximately 90% of the cases are diffuse large B-cell lymphoma (DLBCL). In recent years, the incidence of PCNSL has significantly increased in women and older men. Although advanced treatments such as high-dose methotrexate (HD-MTX) and targeted agents have been introduced, the prognosis of these patients remains poorer than those with other forms of non-Hodgkin's lymphoma. Twelve cases of Chinese PCNSL were analyzed to detect their genetic alterations using whole-exome sequencing (WES). We identified 448 potential somatic single nucleotide variants (SNVs) with a median of 12 SNVs per PCNSL sample and 35 small indels with potentially protein-changing features in 9 PCNSL samples. We found that myeloid differentiation factor 88 (MYD88) had the highest mutation frequency, which affected the activity of the nuclear factor-κB (NF-κB) pathway. PCNSL samples with low-density lipoprotein receptor-related protein 1B (LRP1B) mutations had a higher mutation rate than samples with wild-type LRP1B. Polycystic kidney and hepatic disease 1 (PKHD1), the causal gene of autosomal recessive polycystic kidney disease (ARPKD), was identified in 2 PCNSL cases and exhibited missense mutations. Pathway analysis revealed enrichment in pathways associated with central carbon metabolism in cancer, renal cell carcinoma, nicotine addiction, bladder cancer, and long-term depression. WES revealed significantly mutated genes associated with the molecular mechanisms of PCNSL, which could serve as therapeutic targets to improve patient outcomes.

Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract.

Neuroendocrine carcinomas of the gastrointestinal tract (GI-NECs) remain a disease of grim prognosis with limited therapeutic options. Their molecular characteristics are still undefined. This study aimed to explore the underlying genetic basis and heterogeneity of GI-NECs. Comprehensive genomic analysis using whole-exome sequencing was performed on 143 formalin-fixed, paraffin-embedded samples of surgically resected GI-NEC with a thorough histological evaluation. Mutational signatures, somatic mutations, and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes. Survival analysis was conducted to identify the independent factors. In total, 143 GI-NECs were examined: the stomach, 87 cases (60.8%); the esophagus, 29 cases (20.3%); the colorectum, 20 cases (14.0%); and the small intestine, 7 cases (4.9%). Eighty-three (58.0%) and 60 (42.0%) cases were subclassified into small cell and large cell subtypes, respectively. GI-NECs showed distinct genetic alterations from their lung counterparts and non-neuroendocrine carcinomas in the same locations. Obvious heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across anatomic locations rather than histological subtypes. Except for tumor protein p53 (TP53) and retinoblastoma 1 (RB1), the most frequently mutated genes in the stomach, esophagus, colorectum, and small intestine were low-density lipoprotein receptor-related protein 1B (LRP1B), notch receptor 1 (NOTCH1), adenomatosis polyposis coli (APC), catenin beta 1 (CTNNB1), respectively. Mutations in the WNT-β-catenin, NOTCH and erythroblastic leukemia viral oncogene B (ERBB) pathways were prevalently identified in gastric, esophageal, and colorectal NECs, respectively. Importantly, 104 (72.7%) GI-NECs harbored putative clinically relevant alterations, and non-gastric location and RB1 bi-allelic inactivation with copy number alterations were identified as two independent poor prognostic factors. Furthermore, we found that tumor cells in GI-NECs first gain clonal mutations in TP53, RB1, NOTCH1 and APC, followed by subsequent whole-genome doubling (WGD) and post-WGD clonal mutations in LRP1B, CUB and Sushi multiple domains 3 (CSMD3), FAT tumor suppressor homolog 4 (FAT4) and erb-b2 receptor tyrosine kinase 4 (ERBB4), and finally develop subclonal mutations. GI-NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations. Moreover, potentially actionable alterations and prognostic factors were revealed for GI-NECs.

Potential predictive value of comutant LRP1B and FAT for immune response in non-small cell lung cancer: LRP1B and FAT comutation enhance immune response

BackgroundPreliminary investigation revealed that Low-density lipoprotein receptor-related protein 1b (LRP1B) and FAT atypical cadherin (FAT) family mutation might serve as immune regulators under certain tumor microenvironment. Experimental designWe curated a total of 70 non-small cell lung cancer (NSCLC) patients who harbored alterations in LRP1B and/or FAT family (FAT1/2/3/4) based on next-generation sequencing (NGS) to analyze multiple-dimensional data types, including comutant status, tumor mutation burden (TMB), programmed death receptor ligand 1 (PD-L1) expression, T cell-inflamed gene expression profiling (GEP) and therapy response. Results20 patients with co-occurring mutations in LRP1B and FAT1/2/3/4 revealed a relatively higher TMB level of 17.05 mut/Mb compared with 7.60 mut/Mb and 8.80 mut/Mb in single LRP1B and FAT mutation groups, respectively. LRP1B and FAT members showed specifically enriched T cell-inflamed genes and the co-occurring mutant TP53 status in NSCLC patients who harbor LRP1B/FAT comutations. ConclusionsThis work provides evidence that co-occurring mutations of LRP1B and FAT in NSCLC may serve as a group of potential predictive factors in guiding immunotherapy on the basis of their association with TMB status.

Downregulation of Low-density lipoprotein receptor-related protein 1B (LRP1B) inhibits the progression of hepatocellular carcinoma cells by activating the endoplasmic reticulum stress signaling pathway

ABSTRACT Hepatocellular carcinoma (HCC) has a high recurrence rate and mortality rate even after surgery. Low-density lipoprotein receptor-related protein 1B (LRP1B) has proven to be involved in tumor development and progression of multiple malignancies. However, the function of LRP1B in HCC progression has not been fully elucidated. Thus, we conducted this study to explore the relationship between LRP1B and HCC. Bioinformatic analyses implied that LRP1B was highly expressed in HCC tissues. High LRP1B expression was shown to be related to poor outcomes and the determination of HCC patients’ tumor stage. LRP1B deletion impeded the proliferation, migration, and invasion of HCC cells. Further investigation demonstrated that silencing LRP1B expression enhanced the sensitivity of HCC cells to doxorubicin. LRP1B deletion inhibited HCC progression by regulating the PERK-ATF4-CHOP signaling pathway. Additionally, we probed the genomic alterations of LRP1B in HCC and the impact on the prognosis of patients. Collectively, our results suggest that LRP1B plays an essential role in the promotion of HCC progression by regulating the PERK-ATF4-CHOP signaling pathway, which is a potential prognostic biomarker and a promising therapeutic target of HCC.

Genome-Wide Association Study of Body Weight Traits in Inner Mongolia Cashmere Goats.

Objective: Body weight is an important economic trait for a goat, which greatly affects animal growth and survival. The purpose of this study was to identify genes associated with birth weight (BW), weaning weight (WW), and yearling weight (YW).Materials and Methods: In this study, a genome-wide association study (GWAS) of BW, WW, and YW was determined using the GGP_Goat_70K single-nucleotide polymorphism (SNP) chip in 1,920 Inner Mongolia cashmere goats.Results: We discovered that 21 SNPs were significantly associated with BW on the genome-wide levels. These SNPs were located in 10 genes, e.g., Mitogen-Activated Protein Kinase 3 (MAPK3), LIM domain binding 2 (LDB2), and low-density lipoprotein receptor-related protein 1B (LRP1B), which may be related to muscle growth and development in Inner Mongolia Cashmere goats. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that these genes were significantly enriched in the regulation of actin cytoskeleton and phospholipase D signaling pathway etc.Conclusion: In summary, this study will improve the marker-assisted breeding of Inner Mongolia cashmere goats and the molecular mechanisms of important economic traits.

LRP1B Expression as a Putative Predictor of Response to Pegylated Liposomal Doxorubicin Treatment in Ovarian Cancer

Background: Pegylated liposomal doxorubicin (PLD) is among the most active therapies for recurrent/progressive ovarian cancer (OC). Low-density lipoprotein receptor-related protein 1B (LRP1B) is one of the 10 most significantly deleted genes in human cancers. It mediates endocytosis of several factors from the cellular environment including liposomes. Although the LRP1B role in cancer has not been fully disclosed, its contribution to resistance to liposomal therapies has been hypothesized. This study aimed to evaluate the impact of LRP1B protein as a possible marker of response to PLD in patients with OC. Methods: LRP1B expression and response to PLD were analyzed in OC cell lines by qRT-PCR and PrestoBlue viability assay, respectively. LRP1B protein expression was evaluated for the first time, in tumor samples from PLD-treated patients and controls (other chemotherapies) by immunohistochemistry. Association of LRP1B staining score (determined based on intensity and percentage of positively stained cells) with clinicopathological features, response to therapy and survival outcomes was evaluated. Results: OC cells with increased expression of LRP1B were more sensitive to PLD. LRP1B staining score was associated with clinicopathological features, response to therapy, and survival outcomes. Higher LRP1B levels were associated with prolonged progression-free survival. This association was more evident in patients treated with PLD and in responders to PLD. Conclusion: Our results support a possible role of LRP1B as a predictor of response to PLD in patients with OC.

P70.19 Clinicopathologic Characteristics of Patients With LRP1B Mutations in Chinese Non-Small Cell Lung Cancer Patients

The low-density lipoprotein receptor-related protein 1B (LRP1B), which encoding endocytic LDL-family receptor, is among the top 10 significantly mutated genes in human cancer. It has been demonstrated that LRP1B could bind to multiple extracellular ligands. Frequently inactivationmutation of LRP1B was observed in melanoma, lung cancer, esophagus squamous-cell carcinoma, head and neck squamous cancer, gastric cacner, and so on. The aim of this study is to investigate mutations and prognosis of non-small-cell lung cancer (NSCLC) harboring LRP1B mutations.

Correlation between LRP1B Mutations and Tumor Mutation Burden in Gastric Cancer.

Background It has been shown that low-density lipoprotein receptor-related protein 1B (LRP1B) mutations correlate with tumor mutation burden (TMB) and prognosis in patients with melanoma and non-small-cell lung cancer, while the relationship between LRP1B mutations and TMB in gastric cancer needs further study. This study is aimed at exploring the relationship between LRP1B mutations and TMB in gastric cancer. Methods Mutation frequency profiles of the genes in patients with gastric cancer in TCGA-STAD dataset were analyzed by bioinformatics analysis. The relationship among LRP1B mutations, TMB, and patient clinical features in gastric cancer was investigated by the chi-square test. The TMB prediction capacity based on LRP1B mutation status was evaluated by ROC curves. ResultsLRP1B is one of the top 10 genes with high gene mutation frequency in gastric cancer. The mutation status of LRP1B in gastric cancer patients was significantly correlated with age and TP53 and MUC16 mutation status. The result of ROC curve analysis revealed that the mutation status of LRP1B could be considered as an indicator of the degree of TMB in patients with gastric cancer. Conclusion This study presented the relationship between TMB and LRP1B mutations in gastric cancer, providing a novel perspective for gastric cancer prognosis and therapy.

LRP1B: A Giant Lost in Cancer Translation.

Low-density lipoprotein receptor-related protein 1B (LRP1B) is a giant member of the LDLR protein family, which includes several structurally homologous cell surface receptors with a wide range of biological functions from cargo transport to cell signaling. LRP1B is among the most altered genes in human cancer overall. Found frequently inactivated by several genetic and epigenetic mechanisms, it has mostly been regarded as a putative tumor suppressor. Still, limitations in LRP1B studies exist, in particular associated with its huge size. Therefore, LRP1B expression and function in cancer remains to be fully unveiled. This review addresses the current understanding of LRP1B and the studies that shed a light on the LRP1B structure and ligands. It goes further in presenting increasing knowledge brought by technical and methodological advances that allow to better manipulate LRP1B expression in cells and to more thoroughly explore its expression and mutation status. New evidence is pushing towards the increased relevance of LRP1B in cancer as a potential target or translational prognosis and response to therapy biomarker.

Abstract 356: Association of LRP1B mutation with tumor mutation burden and survival in bladder cancer patients treated with immune checkpoint inhibitors

Abstract Background: Bladder cancer is a common genitourinary malignancy worldwide. Immune checkpoint inhibitors(ICIs) including atezolizumab, pembrolizumab, nivolumab have shown durable responses and have been approved by FDA. However ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. Mutations of LRP1B(The low-density lipoprotein receptor-related protein 1B) are frequently seen in solid tumors and have been reported to be associated with higher tumor mutation burden(TMB) and prolonged survival in NSCLC, melanoma and liver cancer. The association between LRP1B mutation and survival in bladder cancer is unknown. Methods: The association between LRP1B mutation with TMB was analyzed in bladder cancer patients from the public immunotherapy-treated cohort published by Miao et. al as well as a clinical cohort from 3D Medicines database involving 118 Chinese patients. Wilcoxon test was used for the comparison of TMB. Overall survival(OS) and progression-free survival (PFS) analyses were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. Statistical significance was set at p = 0.05. Results: 15%(5/33) bladder cancer patients in the public immunotherapy-treated cohort and 18.6% (22/118) patients in the clinical cohort harbored LRP1B mutation. LRP1B mutation is associated with higher TMB in both public cohort(p=0.028) and clinical cohort(p=0.003). Survival analysis in the public cohort demonstrated that LRP1B mutation resulted in significantly longer OS ( 16.8 vs 8.08 months; HR, 0.16; p=0.043) and a increasing trend on PFS without significant difference (15.9 vs 4.1 months; HR, 0.62; P = 0.39) in bladder cancer patients treated with ICIs. Conclusions: This study shows that LRP1B mutation is relatively common and correlated with higher TMB in bladder cancer. LRP1B mutation may serve as a predictive biomarker of ICI benefit in bladder cancer. Citation Format: Mengmei Yang, Wenzhuan Xie, Mengli Huang, Peng Wu. Association of LRP1B mutation with tumor mutation burden and survival in bladder cancer patients treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 356.

Association of LRP1B mutants with immune biomarkers in Chinese non-small cell lung cancer patients.

e21060 Background: LRP1B (low-density lipoprotein receptor-related protein 1B) is frequently mutated in non-small cell lung cancer (NSCLC). Previous studies showed LRP1B mutations were associated with prolonged survival in melanoma and NSCLC immunotherapy cohort. Higher tumor mutation burden was found in LRP1B mutated patients, suggesting potential benefit of immunotherapy. Herein, we investigate the relationship of LRP1B and immunotherapy biomarker in lager cohort of Chinese and Western NSCLC patients. Methods: Next-generation sequencing data and clinical data were collected from 1053 TCGA NSCLC patients (Western cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 1056 Chinese pan-cancer patients (Chinese cohort). Both LRP1B mutation ratio and TMB were calculated on the two cohorts following the same criteria. TMB-H was defined as the top quartile of all TMB values. Results: In total, 208 (20%) of the 1056 Chinese patients and 385 (37%) of the 1053 Western patients had at least one mutation of LRP1B genes (LRP1B mutant group). The frequency of LRP1B mutation between Western cohort and Chinese cohort had significant difference (20% vs. 37%, p＜0.001). In both cohorts, TMB was higher in the LRP1B mutant group compared to non-LRP1B mutant group. In Chinese cohort, PD-L1 positive was not associated with LRP1B mutation. Patients with LRP1B mutation were associated with prolonged survival in Western immunotherapy cohort. Conclusions: Our study provided a landscape of LRP1B mutations in a much larger Chinese NSCLC group, which could be a valuable complement to TCGA dataset and previous study. Results of our study was consistent with previous studies. Both in Chinese and Western cohorts, the higher TMB in LRP1B mutant patients suggested potential efficacy from immunotherapy of LRP1B mutant group. This result and the potential predictive value of LRP1B in immunotherapy should be validation in a larger Chinese LRP1B mutant cohort in the further.

Analysis of LRP1B as a potential biomarker for colorectal cancer immunotherapy.

e15521 Background: Low-density lipoprotein receptor-related protein 1B (LRP1B), a putative tumor suppressor, is one of the most frequently altered gene in cancer. Recently, there are emerging evidences that LRP1B is involved in sensitivity to melanoma and non-small cell lung cancer immunotherapy. Here we explored the relationship between LRP1B mutation and potential effect of immunotherapy for colorectal cancer (CRC) based on multidimensional data. Methods: Next-generation sequencing (NGS) data of CRC patients (n = 536) from TCGA and Chinese clinical dataset (n = 249) was used to evaluate tumor mutational burden (TMB) differences between LRP1B mutation group and wildtype group. TMB was calculated as the total count of nonsynonymous mutations in coding sequence. Neoantigens of CRC samples (n = 214) were obtained from The Cancer Immunome Atlas. In addition, we investigated the association of LRP1B mutation with 30 immune-related genes, which were classified into 3 categories: immune checkpoint, T-effector and interferon-γ gene signature, and T cell receptor. Results: 22.95% (123/536) patients in TCGA harbored LRP1B mutation. In the Chinese cohort, the LRP1B mutation ratio (24.50%, 61/249) was similar to TCGA. The TMB level of LRP1B mutation group in both TCGA and Chinese cohort was significantly higher than wild-type group (P &lt; 0.001). The TNB between two group is also showed a significant difference (P &lt; 0.001) in TCGA. Of the 30 immune-related genes, 27 (90.0%) genes are differentially expressed (P &lt; 0.05) and all 27 differentially expressed genes have higher expression levels in LRBP1-mutated samples in comparison with wild-type ones. Conclusions: LRBP1-mutated CRC patients have a higher TMB, TNB and show higher expression level with immune-related genes. These results indicated that LRP1B mutation may serve as a potential biomarker of ICI benefit in CRC patients. Moreover, further clinical insights and prospective validation studies are warranted.

Clinicopathological and molecular characteristics of patients with hypermutant lung cancer: A retrospective cohort study.

Tumor mutation burden (TMB) is an independent indicator used to select patients sensitive to immunotherapy. The present study aimed to investigate the clinicopathological and molecular characteristics of patients with hypermutant lung cancer to identify an economical, simple and complementary method for predicting TMB and immunotherapy responses. In total, 1,000 patients with lung cancer were randomly selected, and their samples were submitted to next-generation sequencing, with their TMB status reviewed. The threshold of hypermutation was set to 17.24 mutations (muts)/Mb. The proportion of smokers was higher in the hypermutant cohort (n=67) compared with in the non-hypermutant cohort (n=933; 85.1 vs. 46.6%; P<0.0001). Compared with in the non-hypermutant cohort, the proportion of squamous cell carcinoma cases and small cell lung cancer cases was higher in the hypermutant cohort (22.4 vs. 13.1% and 6.0 vs. 2.6%, respectively). In addition, compared with in the non-hypermutant cohort, mutations in the low-density lipoprotein receptor-related protein 1B were more frequently observed in the hypermutant cohort (67.2 vs. 14.3%; P<0.0001). A similar trend was obtained for all genes tested, except for the EGFR gene. Furthermore, in the hypermutant cohort, the prevalence of microsatellite instability was extremely high (9.0%). The mutation frequency in DNA damage response (DDR) genes was notably higher in the hypermutant cohort, where several DDR-associated genes were enriched, compared with in the non-hypermutant cohort. The enrichment analysis revealed a strong association between mutations in Notch signaling and high TMB. To the best of our knowledge, the present study is the first to comprehensively investigate the clinical and genetic characteristics of patients with hypermutant lung cancer in a Chinese population. The results of the current study suggested that hypermutant lung cancer exerted distinctive clinical and genetic features, which may be used as complementary indicators for screening patients sensitive to immunotherapy.

LRP1B mutation: a novel independent prognostic factor and a predictive tumor mutation burden in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies globally and the second leading cause of cancer-related death. Low-density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is one of the commonly mutated genes in HCC, but its role in HCC remains unclear. In this study, we analyzed the role of LRP1B mutation in HCC. The bioinformatics results show that LRP1B had a frequency of mutation in HCC patients, and LRP1B mutation was associated with a higher tumor mutation burden (TMB), and survival analysis proved that the prognosis of HCC patients with LRP1B mutation was poor. Univariate and multivariate COX regression analysis indicated that LRP1B mutation was an independent risk factor in evaluating HCC patients' prognosis. Correlation analysis showed that LRP1B mutation status was associated with the infiltration of 2 types of immune cells and higher expression of immune checkpoint gene human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) in HCC patients. In summary, the results show that LRP1B mutation is associated with the higher TMB and poor prognosis of patients with HCC, and it was an independent risk factor for clinical outcomes of HCC patients. LRP1B gene mutations can serve as predictors in HCC patients with higher TMB and higher expression of HHLA2. The results of this study will be beneficial to future studies on targeted therapy and immunotherapy for HCC.

Comprehensive molecular profiling to predict clinical outcomes in pancreatic cancer.

Background:Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among common cancers. The genomic landscape of PDAC is defined by four mutational pathways: kirsten rat sarcoma virus (KRAS), cellular tumor antigen p53 (TP53), cyclin dependent kinase inhibitor 2A (CDKN2A), and SMAD family member 4 (SMAD4). However, there is a paucity of data on the molecular features associated with clinical outcomes after surgery or chemotherapy.Methods:We performed comprehensive molecular characterization of tumor specimens from 83 patients with PDAC who received surgery, using whole-exome sequencing and ribonucleic acid sequencing on tumor and matched normal tissues derived from patients. We also systematically performed integrative analysis, combining genomic, transcriptomic, and clinical features to identify biomarkers and possible therapeutic targets.Results:KRAS (75%), TP53 (67%), CDKN2A (12%), SMAD4 (20%), and ring finger protein 43 (RNF43) (13%) were identified as significantly mutated genes. The tumor-specific transcriptome was classified into two clusters (tumor S1 and tumor S2), which resembled the Moffitt tumor classification. Tumor S1 displayed two distinct subclusters (S1-1 and S1-2). The transcriptome of tumor S1-1 overlapped with the exocrine-like (Collisson)/ADEX (Bailey) subtype, while tumor S1-2 mostly consisted of the classical (Collisson)/progenitor (Bailey) subtype. In the analysis of combinatorial gene alterations, concomitant mutations of KRAS with low-density lipoprotein receptor related protein 1B (LRP1B) were associated with significantly worse disease-free survival after surgery (p = 0.034). One patient (1.2%) was an ultrahypermutant with microsatellite instability. We also identified high protein kinase C lota (PRKCI) expression as an overlapping, poor prognostic marker between our dataset and the TCGA dataset.Conclusion:We identified potential prognostic biomarkers and therapeutic targets of patients with PDAC. Understanding these molecular aberrations that determine patient outcomes after surgery and chemotherapy has the potential to improve the treatment outcomes of PDAC patients.