LRP1B and GRM3 expression in colorectal cancer.
Authors: Jayachandran Priya , Yin Jun , Xiu Joanne , Brodskiy Pavel , Arai Hiroyuki , Abraham Jim , Battaglin Francesca , Soni Shivani , Hall Michael J. , Khushman Moh'd M. , Sohal Davendra , Weinberg Benjamin Adam , Goldberg Richard M. , Lou Emil , Zhang Wu , Millstein Joshua , Korn Wolfgang Michael , Lenz Heinz-Josef 
Published: January 2022

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Background: LRP1B is a member of the low-density lipoprotein receptor family and a tumor suppressor found to be downregulated in colon cancer (CRC). GRM3 is a receptor of glutamate, an amino acid and neurotransmitter. Inhibition of GRM3 reduces CRC cell growth. Recent data from CALGB/SWOG 80405 suggests that mutations (MT) of either LRP1B or GRM3 are associated with better and worse overall survival (OS) in patients treated with bevacizumab (Bev), respectively. We investigate the association of LRP1B or GRM3 mRNA levels with outcomes. Methods: A total of 13,780 CRC tumors (male 7,497, female 6,283) underwent comprehensive molecular profiling (Caris Life Sciences). Analyses included next-generation sequencing of DNA (592 genes, NextSeq, WES, NovaSEQ) and RNA (NovaSeq). Significance with multiple correction was indicated with q, otherwise p value. Gene Set Enrichment Analyses (GSEA) were performed (significance p <.05). A Consensus Molecular Subtype (CMS) calling algorithm was developed using mRNA levels (transcripts per million; TPM). Time on treatment (TOT) with Bev was extracted from insurance claims. Results: Male patients had higher GRM3 expression (median TPM.55 vs..52, p <.001). GRM3 and LRP1B were both elevated in brain metastases (1.95 vs..40, q<.01;.53 vs..16, q<.01) and enriched in CMS4 subtype (both p <.001). Overexpression of GRM3 and LRP1B were significantly associated with MSS (.11 vs..07, p <.0001;.54 vs..39, p <.0001) and TMB low status (.11 vs..08, p <.0001;.54 vs..40, p <.0001). For MSS tumors, high LRP1B was associated with lower MT rates of APC (76% vs. 78%), KRAS (49% vs. 51%) and PIK3CA (15% vs. 17%). For MSI tumors, high LRP1B correlated with higher MT of MSH6 (41% vs. 32%), BRCA2 (28% vs. 20%) and PMS2 (12% vs. 6%). MSS tumors with high GRM3 had more APC (79% vs. 75%), less KRAS (47% vs. 52%) and SMAD4 (12% vs. 16%) MT and MSI with high GRM3 carried more APC (42% vs. 35%) and RAD50 (18% vs. 8%) MT. MSS tumors with low LRP1B showed upregulation of the EIF2 pathway while MTOR, RAB, and CDC42 pathways were enriched in MSI with low LRP1B. CDC42 and MTOR pathways were enriched in MSS tumors with low GRM3, and MSI with low GRM3 displayed enrichment of EIF2 and Notch pathways. In MSS tumors, both LRP1B and GRM3 were prognostic and associated with better survival (HR.66, 95% CI [.56-.78], p <.0001 for LRP1B; HR.79, 95% CI [.68-.92], p <.01 for GRM3) and high expression of either one was also associated with better prognosis for patients treated with Bev (HR.85, 95% CI [.70-.92], p <.01 for LRP1B; HR 0.88, 95% CI [.77-.99], p <.05 for GRM3). Conclusions: LRP1B and GRM3 appear to be important regulators in CRC because of their prognostic value and association with response to bevacizumab treatment. Both LRP1B and GRM3 are associated with pathways of cell cycle progression, cell migration, and DNA repair. A better understanding of their role in angiogenic signaling is critical to develop more effective strategies to improve response to bevacizumab or immunotherapy.