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Annals of Surgical Oncology 9:901-906 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Germline SMAD4 or BMPR1A Mutations and Phenotype of Juvenile Polyposis

M.G. Sayed, MD, A.F. Ahmed, MD, J.R. Ringold, BS, M.E. Anderson, BS, J.L. Bair, BS, F.A. Mitros, MD, H.T. Lynch, MD, S.T. Tinley, RN, MS, CGC, G.M. Petersen, PhD, F.M. Giardiello, MD, B. Vogelstein, MD and J.R. Howe, MD

From the University of Iowa College of Medicine (MGS, AFA, JRR, MEA, JLB, FAM, JRH), Iowa City, Iowa; Creighton University (HTL, STT), Omaha, Nebraska; Mayo Clinic (GMP), Rochester, Minnesota; and Johns Hopkins University (FMG, BV), Baltimore, Maryland.

Correspondence: Address correspondence and reprint requests to: James R. Howe, MD, Department of Surgery, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA 52240; Fax: 319-356-8378; E-mail: james-howe{at}uiowa.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Juvenile polyposis (JP) is an inherited condition predisposing to upper gastrointestinal (UGI) polyps and colorectal cancer. Two genes are known to predisose to JP, SMAD4 and bone morphogenetic protein receptor type 1A (BMPR1A). The object of this study was to determine the differences in phenotype of patients with SMAD4 or BMPR1A mutations (MUT+) compared with those without (MUT-).

Methods: DNA was extracted from 54 JP probands and used for polymerase chain reaction of all exons of SMAD4 and BMPR1A. Products were then sequenced and analyzed for mutations. Medical record data were used to create a JP database, and statistical analysis was performed using Fisher’s exact and unpaired t-tests.

Results: Nine of 54 patients had germline SMAD4 mutations, 13 had BMPR1A mutations, and 32 had neither. There were no significant differences between SMAD4+ and BMPR1A+ cases in terms of clinical factors examined, except for a family history of UGI involvement (P < .01). There was a higher prevalence of familial cases in MUT+ patients (P = .09), >10 lower gastrointestinal polyps (P = .06), and frequency of family history of gastrointestinal cancer compared with MUT- patients (P = .01).

Conclusions: Patients with germline SMAD4 or BMPR1A mutations have a more prominent JP phenotype than those without, and SMAD4 mutations predispose to UGI polyposis.

Key Words: Intestinal polyps • Hamartomatous polyps • Polyposis syndromes • Juvenile polyposis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Juvenile polyposis (JP) is a dominantly inherited disorder characterized by the development of hamartomatous polyps throughout the gastrointestinal (GI) tract1 and is associated with an increased risk for GI malignancy.2 The diagnostic criteria for JP are (1) more than five juvenile polyps of the colorectal region, (2) juvenile polyps throughout the GI tract, or (3) any number of juvenile polyps in a patient with a family history of JP.3 Juvenile polyps are the most frequent type of colorectal polyps encountered in childhood and adolescence. Although up to 2% of children and adolescents develop juvenile polyps, these lesions are usually solitary, are unlikely to become malignant, and are not associated with JP.4,5 Reports on the prevalence of JP vary from 1 in 100,0006 to 1 in 160,000, 7 with this wide variation reflecting the absence of population-based data.2

Patients with JP have been categorized into three groups according to phenotype: (1) JP of infancy, (2) JP coli (referring to cases with colonic involvement only), and (3) generalized JP.8 GI involvement within the same JP family can be quite variable, raising the question of whether these categories could represent variable expressivity of the same germline defects.9 The genetic basis of JP remained ambiguous until recently. In 1998, a gene responsible for JP in a large kindred was mapped by genetic linkage to chromosome 18q21.1.10 Sequencing of candidate genes revealed that germline mutations of SMAD4 were present in a proportion of JP patients.11 This finding was confirmed in additional studies,12–15 with the largest revealing a 20% rate of germline mutation in a series of 41 patients.16 SMAD4, also known as MADH4 and DPC4 (deleted in pancreatic cancer 4), is the common intracellular mediator of the transforming growth factor ß (TGF-ß) superfamily signaling pathways.17 A genome screen in four JP families without SMAD4 mutations revealed linkage of a second JP locus with markers on chromosome 10q22—23. Truncating mutations were uncovered in the bone morphogenetic protein receptor 1A gene (BMPR1A; also known as ALK3) from this region in all four families.18 This encodes for a type I serine/threonine kinase receptor that is also a member of the TGF-ß superfamily. In addition, the bone morphogenetic protein (BMP) pathway mediates intracellular signaling through SMAD4. Presently, the influence of SMAD4 and BMPR1A mutations on the phenotype of JP patients is unknown, and the objective of this study was to examine the association of different germline mutations with the clinical features of JP.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population
After informed consent was obtained, peripheral blood samples were drawn from each patient, and genomic DNA was extracted from lymphocytes by using a salting-out procedure.19 Medical record data, including endoscopic, surgical, and pathology reports, were reviewed and entered into a database. This was supplemented by information from JP questionnaires completed by each patient, containing data regarding symptoms, medical history, and family history. Histopathologic slides were also reviewed where available to confirm the diagnosis of JP. The clinical and pathologic fields in the database included age at onset of symptoms, age at diagnosis, presence of multiple (>10) lower GI (LGI) juvenile polyps, whether cases were familial or sporadic, family history of upper GI (UGI) juvenile polyps, or family history of GI cancer. The mean age of onset of symptoms and of diagnosis were determined from the proband of each family, as were the number of polyps present. Probands were considered to be the first affected family member from whom a blood sample was obtained. Families or individuals were considered to have UGI involvement if at least one affected family member with JP had gastric or small-intestinal polyps. Families or individuals were considered to have a family history of GI cancer if a relative with JP developed GI malignancy (including up to third-degree relatives).

Genetic Analysis
All exons and intron/exon boundaries of SMAD4 and BMPR1A were amplified by using DNA from each JP patient by polymerase chain reaction, as previously described.11,18 The amplicons were gel-purified (Qiagen, Valencia, CA) and then cycle-sequenced with an automated sequencer (Applied Biosystems, Foster City, CA). The sequences were analyzed with the Sequencher software (Gene Codes Corp., Ann Arbor, MI) by alignment of each patient sequence to the SMAD4 wild-type sequences. When mutations were detected, sequencing was performed in the reverse direction to confirm the mutation. Statistical analyses of clinical factors with respect to mutation status were performed with the unpaired t-test and Fisher’s exact test. Statistical significance was defined as a P value of <.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Fifty-four JP cases were evaluated, of which 34 (63%) were familial, 12 (22%) were sporadic, and 8 (15%) had incomplete data for classification. The overall mean age of symptoms and diagnosis was 10.8 and 16.3 years, respectively. A family history of UGI juvenile polyps was present in 12 (31%) of 39 cases, multiple (>10) LGI polyps were found in 29 (73%) of 40 cases, and a family history of GI cancer was present in 30 (68%) of 44 patients, where data were available. Clinical factors according to mutation status are listed in Table 1.


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  		TABLE 1. Clinical features and mutation status in JP cases
 
Germline mutations in either SMAD4 or BMPR1A (MUT+) were found in 22 cases (41%), and no mutation of these genes was found in 32 patients (59%; MUT-). SMAD4 mutations were found in 9 (16.7%) of 54 cases (designated as SMAD4+). Six of these mutations were microdeletions, and three were substitutions (two missense, one nonsense; Table 2). Thirteen (24%) of 54 cases had BMPR1A mutations identified (BMPR1A+), where 5 were microdeletions and 8 were substitutions (4 missense, 4 nonsense; Table 3).


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  		TABLE 2. SMAD4 mutations found in JP cases
 

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  		TABLE 3. BMPR1A mutations found in JP cases
 
The results of statistical analyses are listed in Table 4. There were no statistically significant differences in clinical factors between BMPR1A+ and MUT- cases, whereas the age of LGI polyposis diagnosis, family history of UGI polyps, and family history of cancer were significantly different between SMAD4+ and MUT- cases. The only significant difference between SMAD4+ and BMPR1A+ cases was the prevalence of family history of UGI polyps, which was 86% for SMAD4+ and 10% for BMPR1A+ cases (P < .01). Because of the similarities between SMAD4+ and BMPR1A+ cases, these groups were combined to make comparisons to MUT- cases to reduce the effect of low numbers of patients in each group. When the groups were combined, the mean age of symptoms for MUT+ cases was 15.3 years (n = 10), compared with 9.2 years (n = 22) for MUT- patients (P = .11). The mean age of diagnosis for MUT+ patients was 21.4 years (n = 14), whereas in the MUT- group, it was 13.1 years (n = 24; P = .05). There was a trend toward a higher frequency of familial cases (89%) and >10 LGI polyps (93%) in MUT+ cases relative to MUT- cases (63% and 62%, respectively), but these differences were not statistically significant. A family history of UGI involvement was a common feature of SMAD4+ cases, with significant differences found between BMPR1A+ (P < .01) and MUT- cases (P < .01). The frequency of a positive family history of GI cancer in MUT+ cases (89%) was significantly higher than that found in MUT- cases (52%; P = .01).


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  		TABLE 4. P values between different mutation status categoriesa
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The discovery of predisposition genes for JP has simplified the screening of at-risk relatives by determining presymptomatically those who are carriers and need surveillance and those who are not affected by this condition.20 Presently, we have identified germline mutations in only 40% of JP cases, and, therefore, presymptomatic testing is possible in the minority of patients. The focus of this investigation was to determine inherent differences in disease characteristics between JP patients with and without germline mutations. These findings would have implications for the clinical and genetic screening of JP patients.21

We found that MUT+ cases generally presented at an older age than MUT- ones (the mean age of onset of symptoms and the mean age of diagnosis in MUT+ cases were 15.3 and 21.4 years, compared with 9.2 and 13.1 years, respectively, in MUT- cases). Our findings in the MUT+ group are in accordance with the observations of Jass et al., 3 who reported that most JP cases present by the second decade of life. Haggitt and Reid22 found that the average age of onset of JP was 18 years. Coburn et al.23 reviewed the literature encompassing 218 cases and estimated that the mean age at diagnosis was 18.5 years. The mean age of symptoms and the mean age of diagnosis for MUT+ were older relative to MUT- cases, despite the higher frequency of familial cases (89% vs. 63%, respectively), and consequently there was an increased awareness of the disease among MUT+ patients. This would seem counterintuitive, because familial patients are more likely to be diagnosed during screening endoscopy than those without a family history. One explanation for this finding would be that the yet undiscovered genes in MUT- JP cases predispose to an earlier age of onset. Alternatively, the sample size is too small for this analysis (n = 34), even though the differences in age at LGI diagnosis were found to be significant between these two groups.

This study showed no significant differences in the clinical factors examined between SMAD4+ and BMPR1A+ cases, except for a higher prevalence of family members having UGI polyps among SMAD4+ patients (86% vs. 10%, respectively; P < .01). There was also a higher frequency of UGI polyps in SMAD4+ cases versus MUT- cases (23%; P < .01). Bussey24 reported that the presence of polyps in the stomach and small intestine is usually accompanied by more severe symptoms in JP patients. In a review of 272 cases of JP by Hofting et al., 25 the most frequently affected site was the colorectal region (98%), whereas stomach involvement was found in 14% of cases, followed by the jejunum and ileum (7%) and the duodenum (2%). Because the generalized form of JP usually causes more severe symptoms (such as greater blood loss and iron-deficiency anemia),26 then it is expected that a higher proportion of MUT+, in particular SMAD4+, cases will have a more florid clinical picture and be associated with these complications. The clinical implication of these findings is that SMAD4+ patients need closer monitoring by upper endoscopy for the development of gastric polyps and cancer, whereas BMPR1A+ and MUT- patients are much less likely to develop these sequelae. However, 10% of BMPR1A patients and 23% of MUT- patients still had family members with UGI juvenile polyps, and they also need UGI tract screening, but at longer intervals, such as every 5 years versus every 1 to 3 years for SMAD4+ patients.

In our series, MUT+ cases showed a higher percentage of multiple (>10) LGI tract polyps (93%), in contrast to MUT- (62%), a difference that approached statistical significance (P = .06). This further suggests that JP patients with SMAD4 or BMPR1A mutations have more pronounced expression of the germline defects in the GI tract. Whether these patients need more frequent colonoscopic screening than MUT- patients will be answered only through long-term follow-up.

A family history of GI cancer was documented in 89% of MUT+ cases but in only 52% of MUT- cases (P = .01). The risk of GI cancer in JP varies among different series. Jarvinen and Franssila1 reported that 9 carcinomas of the colon occurred in 102 patients with JP, for a prevalence of 9%. Bussey24 studied 60 JP cases and found that the frequency of colorectal cancer was 10%. Hofting et al.25 reported an 18% prevalence of GI cancer in their JP patients. The lower figures given by these studies may be explained by the fact that they did not count relatives of affected JP patients with a history of GI cancer. Murday and Slack,27 in a study from St. Mark’s Hospital, estimated that the cumulative risk of colorectal cancer in their JP patients was as high as 68% at age 60. In the largest JP kindred described in the literature, consisting of 117 members, the prevalence of colorectal cancer in affected patients was 38%, the prevalence of UGI cancer of 21%, and the overall risk of GI cancer was 55%.9 Members of this family have germline SMAD4 mutations.11 A similar figure was provided by Jass et al.,3 who found the risk of colorectal cancer in a series including 1032 polyps from 87 JP patients to be approximately 50%. This emphasizes the increased cancer risk in JP cases compared with the general population, where the lifetime risk of colorectal cancer is only 6%.28 The greater risk of family history of GI cancer in MUT+ relative to MUT- families may be due to more MUT- cases being sporadic (37% vs. 11% in MUT+), with shorter follow-up, and to the predisposition to cancer beginning in the proband’s generation. Another important explanation for this increased risk of cancer seen in MUT+ families is that germline SMAD4 or BMPR1A mutations lead to a more severe phenotype of JP.

The mechanism by which polyps form in JP patients has not been established. The SMAD4 protein is a common mediator involved in the TGF-ß, activin, and BMP signal-transduction pathways. Members of the TGF-ß superfamily initiate a wide range of effects on a variety of cell types, including cell differentiation, proliferation, and apoptosis.17,29 Ligands of the TGF-ß superfamily bind to plasma membrane serine/threonine kinase type II receptors, which then complex with type I receptors, causing phosphorylation in a serine- and threonine-rich domain of the type I receptor.30 These activated type I receptors phosphorylate cytoplasmic SMAD proteins (SMAD2 or SMAD3 for TGF-ß; SMAD1, 5, and 8 for BMP), which then associate and form oligomers with SMAD4.31,32 Hetero-oligomers of SMADs and SMAD4 then migrate to the nucleus and regulate transcription in conjunction with DNA-binding proteins.33 How these defects specifically lead to juvenile polyps and cancer is unknown at the present time, but Smad4 heterozygous knock-out mice develop GI cancer and polyps very similar to those seen in JP patients.34 Homozygous Smad4 and Bmpr knock-out mice die early in utero with a lack of mesoderm formation.35–38 Furthermore, the role for BMP in cancer development has not been clearly established in other tumors. These unanswered questions await the identification of new JP genes and further characterization of gene expression in juvenile polyps.


   Acknowledgments
 
Supported by a generous grant from the Roy J. Carver Charitable Trust.


   Footnotes
 
Patients with SMAD4 or BMPR1A mutations represent 41% of juvenile polyposis cases. They have a later age of disease onset, a higher prevalence of multiple lower gastrointestinal polyps, and a higher rate of family history of gastrointestinal cancer. Cases with SMAD4 mutation are more likely to develop upper gastrointestinal polyps.

Received for publication March 15, 2002. Accepted for publication June 17, 2002.


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 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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