Genotype-defined cancer risk in juvenile polyposis syndrome.
BACKGROUND
Germline mutations in SMAD4 and BMPR1A disrupt the transforming growth factor β signal transduction pathway, and are associated with juvenile polyposis syndrome. The effect of genotype on the pattern of disease in this syndrome is unknown. This study evaluated the differential impact of SMAD4 and BMPR1A gene mutations on cancer risk and oncological phenotype in patients with juvenile polyposis syndrome.


METHODS
Patients with juvenile polyposis syndrome and germline SMAD4 or BMPR1A mutations were identified from a prospectively maintained institutional registry. Medical records were reviewed and the clinical patterns of disease were analysed.


RESULTS
Thirty-five patients had germline mutations in either BMPR1A (8 patients) or SMAD4 (27). Median follow-up was 11 years. Colonic phenotype was similar between patients with SMAD4 and BMPR1A mutations, whereas SMAD4 mutations were associated with larger polyp numbers (number of patients with 50 or more gastric polyps: 14 versus 0 respectively). The numbers of patients with rectal polyps was comparable between BMPR1A and SMAD4 mutation carriers (5 versus 17). No patient was diagnosed with cancer in the BMPR1A group, whereas four men with a SMAD4 mutation developed gastrointestinal (3) or extraintestinal (1) cancer. The gastrointestinal cancer risk in patients with juvenile polyposis syndrome and a SMAD4 mutation was 11 per cent (3 of 27).


CONCLUSIONS
The SMAD4 genotype is associated with a more aggressive upper gastrointestinal malignancy risk in juvenile polyposis syndrome.
Department of Colorectal Surgery, Genomic Medicine Institute, Ohio, USA.
E
E
Aytac
B
B
Sulu
B
B
Heald
M
M
O'Malley
L
L
LaGuardia
F H
FH
Remzi
M F
MF
Kalady
C A
CA
Burke
J M
JM
Church
D000293:Adolescent; D000328:Adult; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000601:surgery; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D044483:Intestinal Polyposis / Q000151:congenital* / Q000235:genetics / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000601:surgery; D010641:Phenotype; D012307:Risk Factors; D051901:Smad4 Protein / Q000235:genetics*; D055815:Young Adult
C497796:SMAD4 protein, human; D051901:Smad4 Protein; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I