Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis.
BACKGROUND
Significant proportions of patients with hamartomatous polyposis or with hyperplastic/mixed polyposis remain without specific clinical and molecular diagnosis or present atypically. Assigning a syndromic diagnosis is important because it guides management, especially surveillance and prophylactic surgery.


OBJECTIVE
To systematically classify patients with unexplained hamartomatous or hyperplastic/mixed polyposis by extensive molecular analysis in the context of central rereview of histopathology results.


METHODS
Prospective, referral-based study of 49 unrelated patients from outside institutions (n = 28) and at a comprehensive cancer center (n = 21), conducted from May 2, 2002, until December 15, 2004. Germline analysis of PTEN, BMPR1A, STK11 (sequence, deletion), SMAD4, and ENG (sequence), specific exon screening of BRAF, MYH, and BHD, and rereview of polyp histology results were performed.


METHODS
Molecular, clinical, and histopathological findings in patients with unexplained polyposis.


RESULTS
Of the 49 patients, 11 (22%) had germline mutations. Of 14 patients with juvenile polyposis, 2 with early-onset disease had mutations in ENG, encoding endoglin, previously only associated with hereditary hemorrhagic telangiectasia; 1 had hemizygous deletion encompassing PTEN and BMPR1A; and 1 had an SMAD4 mutation. One individual previously classified with Peutz-Jeghers syndrome had a PTEN deletion. Among 9 individuals with an unknown hamartomatous polyposis, 4 had mutations in STK11 (1), BMPR1A (2), and SMAD4 (1). Of the 23 patients with hyperplastic/mixed polyposis, 2 had PTEN mutations. Substantial discrepancies in histopathology results were seen.


CONCLUSIONS
Systematic molecular classification of 49 patients with unexplained hamartomatous or hyperplastic polyposis uncovered a potential novel susceptibility gene, ENG, for juvenile polyposis. Importantly, given the substantial proportion of patients found to have germline mutations, more extensive analysis of the known susceptibility genes is indicated. Rereview of histology results by a dedicated gastrointestinal pathologist should be considered routinely, as organ-specific surveillance rests on defining syndromic diagnosis.
Sweet
Kevin
K
Clinical Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, USA.
Willis
Joseph
J
Zhou
Xiao-Ping
XP
Gallione
Carol
C
Sawada
Takeshi
T
Alhopuro
Pia
P
Khoo
Sok Kean
SK
Patocs
Attila
A
Martin
Cossette
C
Bridgeman
Scott
S
Heinz
John
J
Pilarski
Robert
R
Lehtonen
Rainer
R
Prior
Thomas W
TW
Frebourg
Thierry
T
Teh
Bin Tean
BT
Marchuk
Douglas A
DA
Aaltonen
Lauri A
LA
Eng
Charis
C
D000091162:AMP-Activated Protein Kinase Kinases; D000293:Adolescent; D000328:Adult; D015703:Antigens, CD; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D002648:Child; D000071063:Endoglin; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000145:classification / Q000235:genetics* / Q000473:pathology; D006801:Humans; D044483:Intestinal Polyposis / Q000145:classification / Q000235:genetics* / Q000473:pathology; D007417:Intestinal Polyps / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010580:Peutz-Jeghers Syndrome / Q000145:classification / Q000235:genetics* / Q000473:pathology; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011956:Receptors, Cell Surface; D051901:Smad4 Protein / Q000235:genetics; D013577:Syndrome; D025521:Tumor Suppressor Proteins; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C476078:FLCN protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D051901:Smad4 Protein; D025521:Tumor Suppressor Proteins; D019010:Vascular Cell Adhesion Molecule-1; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human