Abstract 1715P
Background
SMAD4 mutations have been associated with worse prognosis and metastatic disease in patients with various cancers. The differences in mutation profiles of SMAD4 gene in pan-cancer can help understand pathogenesis, prognosis, and identify targets for therapy.
Methods
Using commercial NGS assays, we retrospectively analyzed genomic DNA alterations in normal-paired samples from 3957 patients with malignancies between 2019 to 2022, and alterations including single-base substitution, short and long insertion/deletions, copy number variations, gene fusions and rearrangements.
Results
SMAD4 gene was altered in 6.7% (264 of 3957) of all solid tumors. The frequency of SMAD4 variations was assessed in multiple cancer types, including pancreatic cancer 20.5% (30/146), colorectal cancer 18.7% (122/654), cholangiocarcinoma 11.3% (15/133), cervix tumor 5.8% (3/52), cervical cancer 3.4% (4/117), liver cancer 3.2% (7/221), gastric carcinoma 3.1% (12/386), breast cancer 2.2% (1/45), non-small cell lung cancer 1.7% (26/1512), renal carcinoma 1.3% (1/77) and ovarian cancer 1% (1/135). Furthermore, in our cohort, A total 347 genetic alterations were identified in 264 patients, including 188 missense (54.2%), 56 nonsense (16.1%), 43 frameshift (13.3%), 37 copy number alterations (10.7%), 12 splicing (3.5%), 8 deletion (2.3%), 2 insertion (0.6%) and 1 stop-loss (0.3%). Among these patients, 10.2% (27/264) of patients had metastatic disease at the time of initial biopsy, including colorectal cancer 48.1% (13/27), pancreatic cancer 33.3% (9/27), gastric carcinoma 7.4% (2/27), non-small cell lung cancer 7.4% (2/27) and cholangiocarcinoma 3.7% (1/27).
Conclusions
SMAD4 deleterious mutations are highly diverse and present at low to moderate frequencies across many cancers. SMAD4 mutations may represent a more sensitive biomarker to identify patients at greater risk for developing metastatic disease and are likely involved in the transformation from localized to metastatic disease.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
The Fund of Chengdu Municipal Health Commission, (NO.2020067).
Disclosure
All authors have declared no conflicts of interest.