Integrated in silico analysis of LRP2 mutations to immunotherapy efficacy in pan-cancer cohort

Abstract

Purpose Immunotherapy has emerged as a novel therapy, while many patients are refractory. Although, several biomarkers have been identified as predictive biomarkers for immunotherapy, such as tumor specific genes, PD-1/PD-L1, tumor mutation burn (TMB), and microsatellite instability (MSI), results remain unsatisfactory. The aim of this study is to evaluate the value of LRP2 mutations in predicating cancer immunotherapy. Methods We investigated the characteristics of low-density lipoprotein receptor-related protein 2 (LRP2) mutation in the cancer genome atlas (TCGA) and explored the potential association of LRP2 mutations with immunotherapy. Characteristics of LRP2 mutations in 33 cancer types were analyzed using large-scale public data. The association of LRP2 mutations with immune cell infiltration and immunotherapy efficacy was evaluated. Finally, a LPR2 mutation signature (LMS) was developed and validated by TCGA-UCEC and pan-cancer cohorts. Furthermore, we demonstrated the predictive power of LMS score in independent immunotherapy cohorts by performing a meta-analysis. Results Our results revealed that patients with LRP2 mutant had higher TMB and MSI compared with patients without LRP2 mutations. LRP2 mutations were associated with high levels of immune cells infiltration, immune-related genes expression and enrichment of immune related signaling pathways. Importantly, LRP2-mutated patients had a long overall survival (OS) after immunotherapy. In the endometrial cancer (EC) cohort, we found that patients with LRP2 mutations belonged to the POLE and MSI-H type and had a better prognosis. Finally, we developed a LRP2 mutations signature (LMS), that was significantly associated with prognosis in patients receiving immunotherapy. Conclusion These results indicated that LRP2 mutations can serve as a biomarker for personalized tumor immunotherapy. Importantly, LMS is a potential predictor of patients’ prognosis after immunotherapy.

A multi-variable predictive warning model for cervical cancer using clinical and SNPs data

“…Multiple studies have shown that small structural differences in HSPG2 across diseases have antagonistic effects on tumor formation and metastasis; intact perlecan promotes the development of a vascular supply that supports tumor cell proliferation and the development of a variety of cancers, whereas bioactive perlecan fragments inhibit tumor development by targeting its vascular supply ( 22 , 23 ). LRP2 (rs2302694) mutations were detected in a range of cancers, with melanoma (28.18%), uterine sarcoma (17.99%), and lung squamous cell carcinoma (16.32%) with the highest mutation rates ( 24 ). A pan-cancer study found that LRP2 mutations were linked with increased immune cell infiltration, immune checkpoint gene expression, and significant enrichment of immune-related signaling pathways, as well as a better prognosis, compared to individuals who did not have LRP2 mutations ( 24 ).…”

“…LRP2 (rs2302694) mutations were detected in a range of cancers, with melanoma (28.18%), uterine sarcoma (17.99%), and lung squamous cell carcinoma (16.32%) with the highest mutation rates ( 24 ). A pan-cancer study found that LRP2 mutations were linked with increased immune cell infiltration, immune checkpoint gene expression, and significant enrichment of immune-related signaling pathways, as well as a better prognosis, compared to individuals who did not have LRP2 mutations ( 24 ). Depletion of Lama5 (rs148927246, rs2274933) in lymph node stromal cells controls immunological responses to T cell migration and function, encourages branching angiogenesis, and modifies Notch signaling, which facilitates colorectal cancer spread to the liver ( 25 , 26 ).…”

Antibrush Border Antibody Disease: A Case Series

“… 3 LRP2/megalin is expressed in a wide range of tissues, including the choroid plexus, the lung alveoli, the thyroid and parathyroid glands, and retina, in addition to proximal tubular cells within the kidney, and has been implicated in tumorigenesis in a range of human cancers, including colorectal cancer, melanoma, and lung cancer. 16 , 17 , 18 However, data remain limited in determining an association between malignancy and ABBA disease.…”

Integrative analyses of genes related to liver ischemia reperfusion injury

“…LRP2 is a coreceptor used to control acoustic hedgehog signaling in development and disease [ 38 ]. Mutations in LRP2 can be used as a biomarker for personalized tumor immunotherapy [ 39 ]. P2RY6, a receptor for nucleotide uridine 5′ -diphosphate, has been implicated in various human diseases, including obesity and autoimmune diseases [ 40 ].…”