Loss of functionSMAD4nonstop mutations in human cancer

Abstract

Background: SMAD4 is a tumour suppressor gene that is mutated in a variety of cancers. SMAD4 nonstop mutations, which convert stop codons to sense codons that extend transcription, have been identified in genomic databases but have not been characterised in human pathology samples. The frequency of SMAD4 nonstop mutations and the consequences of nonstop mutations on SMAD4 protein expression are unknown. Methods: We retrospectively analysed our cancer sequencing database of 38,002 tumour specimens and evaluated the spectrum of SMAD4 mutations. SMAD4 protein expression was evaluated by immunohistochemistry in tumours with SMAD4 nonstop mutations. Results: In total, 1956 SMAD4 mutations were identified in 1822 tumours. SMAD4 mutations were most common in tumours of the gastrointestinal tract and included nonsense variants (n = 344), frameshift indels (n = 258), splice site variants (n = 104), and missense variants at codon R361 (n = 245). In a subset of cases with immunohistochemistry, SMAD4 expression was lost in 23 of 25 tumours (92%) with protein truncating variants and in 7 of 27 tumours (26%) with missense variants. Four cases harboured SMAD4 nonstop mutations. SMAD4 nonstop mutations were identified in two pancreatic adenocarcinomas, one colonic adenocarcinoma, and one nonsmall cell lung carcinoma. Immunohistochemistry demonstrated loss of SMAD4 protein expression in each of the four tumours with SMAD4 nonstop mutations. Conclusion: SMAD4 nonstop mutations are associated with loss of SMAD4 protein expression in multiple tumour types. SMAD4 nonstop mutations should be clinically interpreted as pathogenic loss of function alterations when identified in cancer sequencing panels.

Amyloids “at the border”: deep mutagenesis and random sequence extension reveal an incomplete amyloid-forming motif in Bri2 that turns amyloidogenic upon C-terminal extension

“…Frameshift mutations and stop-loss mutations, also known as nonstop mutations, have been pin-pointed as causative variants in several pathologies (Mignogna et al , 2022; Bauer et al , 2023; Vaché et al , 2023; Rebelo et al , 2016). Nonstop mutations constitute ∼0.2% of codon-changing mutations (Hamby et al , 2011) and often lead to mRNA degradation by the non-stop mediated-decay machinery (Monaghan et al , 2023).…”