Determining oncogenic patterns and cancer predisposition through the transcriptomic profile in Mitchell–Riley syndrome with heterotopic gastric mucosa and duodenal atresia: a case report

Abstract

Background Homozygous mutations in the transcription factor RFX6 are the cause of the Mitchell–Riley syndrome (MRS) associating neonatal diabetes, congenital digestive system, such as biliary atresia, pancreatic hypoplasia, duodenal and/or jejunal atresia, intestinal malrotation, gallbladder aplasia, cholestasis. A constitutive inactivation of RFX6 leads also to gastric heterotopia. Application of RNA-seq in human diseases may help to better understand pathogenic mechanism of diseases and to predict the risk of developing chronic disorders and personalizing their prevention and treatment. We evaluated oncogenic patterns and cancer predisposition using the transcriptomic profile in a case of MRS with neonatal diabetes, duodenal atresia, and extensive intestinal tract gastric heterotopia. Results We signalled the interactors of RFX6 with other up and downregulated genes, that may be interested in severity of diabetic condition, in multi-organs impairment and cancer predisposition. Furthermore, several dysregulated genes are involved in biological processes that can lead to promote cancer including “Evading apoptosis” (BAD, BBC3, EGF, FGFR2, FLT3LG, HMOX1, HRAS, IFNAR2, IGF1R, IL12RB1, IL13RA1, IL15, IL2RB, IL2RG, IL6R, KEAP1, MGST1, PDGFA, PDGFRB, PIK3R3, RALB, RALGDS, RASSF1, SOS1, TGFA, TXNRD3), “Proliferation” (APC, BRAF, CCND2, CCND3, CCNE2, FGFR2, FLT3LG, FZD1, FZD6, HMOX1, HRAS, IGF1R, KEAP1, LRP6, MAPK3, MGST1, PDGFA, PDGFB, PDGFRB, RB1, SOS1, TGFA, TXNRD3, WNT10B), “Sustained angiogenesis” (BRAF, FGFR2, FLT3LG, HRAS, IGF1R, JAG1, MAPK3, NOTCH2, PDGFA, PDGFB, PDGFRB, SOS1, TGFA, TGFB1), “Genomic instability” (BAD, BBC3) and “Insensitivity to anti-growth signals” (SMAD2, TGFB1). We also inspected the signalings and their related genes in cancer, such as “PI3K signaling”, “ERK signaling”, “JAK-STAT signaling”, “Calcium signaling”, “Other RAS signaling”, “WNT signaling”. Conclusions In our MRS patient, we signaled the interactors of RFX6 with other up- and downregulated genes that may be related to severe diabetic condition, multi-organ impairment, and cancer predisposition. Notably, many dysregulated genes may lead to triggering carcinogenesis. The possibility of the patient developing cancer degeneration in heterotopic gastric mucosa and/or additional long-term tumoral sequelae is not excluded. Personalized prevention and treatment strategies should be proposed.

MGST1 Expression Is Associated with Poor Prognosis, Enhancing the Wnt/β-Catenin Pathway via Regulating AKT and Inhibiting Ferroptosis in Gastric Cancer

“…To sum up, MGST1 is equipped to affect the cell functions of GC cells. Moreover, emerging data showed that MGST1 had a confirmed effect on escape to anti-growth signal pathways, 7 and MGST1 was a novel regulator of the Wnt/β-catenin pathway. 4 We examined the proteins in the AKT/GSK-3β signaling pathway of MGST1 downregulated and upregulated AGS and SGC-7901 cells, and the β-catenin protein expressions were reduced in MGST1 knockdown cells and increased in MGST1 upregulated cells.…”

Microsomal glutathione S-transferase 1 targets the autophagy signaling pathway to suppress ferroptosis in gastric carcinoma cells

“…20 A previous analysis of oncogenic patterns and cancer predisposition in GC demonstrated that MGST1 is closely associated with the proliferation of GC cells. 21 Importantly, ferroptosis-associated genes have been demonstrated to predict the prognosis and outcomes of immunotherapy in GC patients, and can also modulate the growth of GC cells. 22 In addition, MGST1 has been reported to repress ferroptotic cancer cell death by binding to ALOX5, thus leading to reduced lipid peroxidation in pancreatic cancer cells.…”

Vitamin D3 deficiency in babies and children with cholestasis

“…Although jaundice in newborns is common and to be expected, persistent jaundice at 14 will usually die within twelve to eighteen months after birth (Song et al, 2012;Squires et al, 2020). Furthermore, biliary atresia can be a clinical characteristic of several hereditary disorders (Sanchez-Valle et al, 2017), including Mitchell Riley syndrome (Calcaterra et al, 2021), Fanconi anaemia complementation group Q (Bogliolo et al, 2013), Zimmermann Lab and syndrome 1, Alagille syndrome (Diaz-Frias & Kondamudi, 2022) and Kabuki syndrome 1 (Masui et al, 2019). Progressive familial intra-hepatic cholestasis and biliary hypoplasia are two other bile duct anomalies that mimic the medical signs of obstructive jaundice with biliary atresia (Gomez-Ospina et al, 2016; Sambrotta et al, 2014).…”