Prevalence of SMAD4 Mutations
Overall Prevalence in Juvenile Polyposis Syndrome
SMAD4 mutations account for approximately 20% of all juvenile polyposis syndrome (JPS) cases, with the overall prevalence of SMAD4 and BMPR1A mutations combined reaching 45% when both point mutations and large deletions are screened. 1
- In the largest series to date of 102 JPS probands, 20 patients (19.6%) had SMAD4 point mutations and 2 additional patients had large SMAD4 deletions, bringing the total SMAD4 mutation prevalence to approximately 21.6% 1
- When combining SMAD4 and BMPR1A mutations together, the overall genetic detection rate in JPS is 45%, with SMAD4 representing roughly half of identified mutations 1
- An earlier study of 54 JPS probands found 9 patients (16.7%) with germline SMAD4 mutations 2
SMAD4 Mutations in Hereditary Hemorrhagic Telangiectasia
SMAD4 mutations cause the juvenile polyposis-HHT overlap syndrome, occurring in 1-2% of all HHT cases, with up to 76% of patients with JPS due to SMAD4 developing features of HHT. 3, 4
- The coexistence of JPS and HHT is exclusively due to SMAD4 mutations, not BMPR1A mutations 4
- Among patients with JPS who carry SMAD4 mutations, 76% manifest clinical features of hereditary hemorrhagic telangiectasia 4
SMAD4 Mutations in Sporadic Colorectal Cancer
SMAD4 mutations in sporadic colorectal cancer show stage-dependent prevalence, with 0% in adenomas, 7-10% in early invasive carcinomas, and 31-35% in metastatic disease. 5
- In a series of 176 colorectal tumors, SMAD4 mutations were found in: 0/40 (0%) adenomas, 4/39 (10%) intramucosal carcinomas, 3/44 (7%) primary invasive carcinomas without metastasis, 6/17 (35%) primary invasive carcinomas with distant metastasis, and 11/36 (31%) distant metastases 5
- The difference between metastatic and non-metastatic carcinomas was statistically significant (p=0.006-0.01) 5
- Loss of the other allele occurred in 19 of 20 (95%) invasive and metastasized carcinomas with SMAD4 mutations 5
Detection Methods and Large Deletions
Large deletions of SMAD4 are less frequent than point mutations but represent important heritable causes of JPS that require multiplex ligation-dependent probe amplification (MLPA) screening in addition to sequencing. 1
- Point mutations detected by sequencing account for the majority of SMAD4 mutations (20/102 probands), while large deletions detected by MLPA add approximately 2% to the detection rate 1
- SMAD4 mutations in JPS-associated polyps show low sensitivity (10% of informative cases) but high specificity for familial juvenile polyposis syndrome 6
Clinical Significance of Mutation Status
Patients with germline SMAD4 mutations have a more prominent JPS phenotype with significantly higher risk of upper gastrointestinal involvement and gastric cancer compared to BMPR1A mutation carriers. 4, 2
- SMAD4 mutation carriers show 73% gastric polyposis prevalence versus 8% in BMPR1A carriers (p<0.001) 4
- All cases of gastric cancer in one cohort occurred exclusively in patients with SMAD4 pathogenic variants 4
- SMAD4 mutations predispose specifically to upper gastrointestinal polyposis with higher family history of UGI involvement (p<0.01) compared to BMPR1A mutations 2