The orphan nuclear receptor NR0B2 could be a novel susceptibility locus associated with microsatellite‐stable, APC mutation‐negative early‐onset colorectal carcinomas with metabolic manifestation

Abstract

Colorectal cancer (CRC) is a high incidence cancer and major cause of cancer mortality. Though disease‐causing tumor suppressors for major syndromes are well characterized, about 10% of CRC is familial but without mutations in known tumor suppressors. We exhaustively screened 100 polyposis families for APC germline mutations and identified 13, which are APC mutation‐negative, microsatellite‐stable (MSS), and with undetectable mutation in known tumor suppressors. Whole exome sequencing in three probands uncovered two with germline frameshift NR0B2 mutations, c.293_301delTTGGGTTGGinsAC and c.227delT. Sanger Sequencing identified a third proband with NR0B2 c.157_166delCATCGCACCT frameshift mutation. All three mutations deleted the C‐terminus activation/repression domain of NR0B2, thus are loss‐of‐function mutations. Real‐time RT‐PCR performed on tumor and matched mucosa of one patient revealed that NR0B2 downstream targets, SMAD3 was derepressed while GLI1 was downregulated in the colonic mucosa compared to healthy controls. Truncated NR0B2 molecule was predicted to have weakened binding with interacting partners SMAD3, GLI1, BCL2, and RXRα, implying perturbation of TGF‐β, Hedgehog, anti‐apoptotic and nuclear hormone receptor signaling pathways. Immunostaining also revealed nuclear retention of the most severely truncated NR0B2 molecule compared to the wildtype. Microsatellite and sequencing analysis did not detect loss of wildtype allele in probands' tumors. The patient who acquired somatic KRAS mutation progressed rapidly whist the other two patients manifested with late‐onset obesity and diabetes. We propose that haploinsufficiency of NR0B2 is associated with a novel CRC syndrome with metabolic phenotypes.

Comparison of some biochemical markers between early‐onset and late‐onset colorectal precancerous lesions: A single‐center retrospective study

“…For instance, orphan nuclear receptor NR0B2 was found to be a novel susceptibility gene for the metabolic manifestation of early-onset CRC. 36 Moreover, a multiomics analysis revealed that the metabolites yielded significant interaction effects between early-onset and late-onset CRC patients. 37 Elevated uric acid is common in patients with obesity, diabetes, and hyperlipidemia or other metabolic syndromes.…”

“…When regarding this difference, the genomic alterations in early‐onset lesions could provide some explanations. For instance, orphan nuclear receptor NR0B2 was found to be a novel susceptibility gene for the metabolic manifestation of early‐onset CRC 36 . Moreover, a multiomics analysis revealed that the metabolites yielded significant interaction effects between early‐onset and late‐onset CRC patients 37 …”

Early‐onset colorectal cancer: why it should be high on our list of differentials

“…Despite this, approximately 80–85% of EOCRCs are sporadic, microsatellite stable tumours 35 . Lam et al 36 . demonstrated a link between NR0B2 frameshift variants and increased susceptibility to microsatellite stable, APC‐negative EOCRC.…”

“…Despite this, approximately 80-85% of EOCRCs are sporadic, microsatellite stable tumours. 35 Lam et al 36 demonstrated a link between NR0B2 frameshift variants and increased susceptibility to microsatellite stable, APC-negative EOCRC. Further, recent molecular research has demonstrated a higher tumour mutational burden and distinct innate immune signature of EOCRC, has correlated specific gene mutations (SSA1, C7, CFD, CXCL3, IL1B, MET and TNS1), and aberrant pathways (wild-type WTN and mutated TGFβ pathway) with poorer overall survival (OS) in EOCRC and has identified accelerated ageing in normal mucosa of EOCRC patients as a potential contributor to carcinogenesis.…”

Data-driven energy landscape reveals critical genes in cancer progression

“…Methylation of MGMT and CALCA could be used as new molecular markers of prognosis in testicular germ cell tumors (TGCT) 27 . Furthermore, the orphan nuclear receptor NR0B2 may represent a new susceptibility locus associated with early-onset colorectal cancer 28 .…”