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Loss of function SMAD4 nonstop mutations in human cancer
Anna H Bauer1,2, David W Basta1, Jason L Hornick1
1Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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 non-small 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.
Insights
SMAD4 nonstop mutations, previously uncharacterized in patient samples, are linked to SMAD4 protein loss in various cancers. These mutations should be recognized as pathogenic loss-of-function alterations in clinical settings.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- SMAD4 is a crucial tumor suppressor gene frequently mutated in diverse cancers.
- Nonstop mutations in SMAD4, which alter stop codons, are known from genomic databases but lack pathological characterization.
- The prevalence and functional impact of SMAD4 nonstop mutations on protein expression remain largely unknown.
Purpose of the Study:
- To investigate the spectrum of SMAD4 mutations in human tumors.
- To determine the frequency and clinical significance of SMAD4 nonstop mutations.
- To assess the effect of SMAD4 nonstop mutations on SMAD4 protein expression.
Main Methods:
- Retrospective analysis of 38,002 tumor specimens from a cancer sequencing database.
- Evaluation of the SMAD4 mutation spectrum, including nonstop variants.
- Immunohistochemistry to assess SMAD4 protein expression in tumors with identified SMAD4 mutations.
Main Results:
- SMAD4 mutations were identified in 1822 tumors, with the highest frequency in gastrointestinal cancers.
- Nonstop SMAD4 mutations were found in four cases: two pancreatic adenocarcinomas, one colonic adenocarcinoma, and one non-small cell lung carcinoma.
- Immunohistochemistry revealed a complete loss of SMAD4 protein expression in all four tumors harboring SMAD4 nonstop mutations.
Conclusions:
- SMAD4 nonstop mutations are associated with loss of SMAD4 protein expression across multiple tumor types.
- These findings support the clinical interpretation of SMAD4 nonstop mutations as pathogenic loss-of-function alterations.
- The study highlights the importance of identifying and characterizing novel SMAD4 mutation types for accurate cancer diagnosis and treatment.
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