James R. Howe

Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis.

Juvenile polyposis (JP; OMIM 174900) is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. Previous studies have demonstrated a locus for JP mapping to 18q21.1 (ref. 3) and germline mutations in the homolog of the gene for mothers against decapentaplegic, Drosophila, (MADH4, also known as SMAD4) in several JP families. However, mutations in MADH4 are only present in a subset of JP cases, and although mutations in the gene for phosphatase and tensin homolog (PTEN) have been described in a few families, undefined genetic heterogeneity remains. Using a genome-wide screen in four JP kindreds without germline mutations in MADH4 or PTEN, we identified linkage with markers from chromosome 10q22–23 (maximum lod score of 4.74, θ=0.00). We found no recombinants using markers developed from the vicinity of the gene for bone morphogenetic protein receptor 1A (BMPR1A), a serine–threonine kinase type I receptor involved in bone morphogenetic protein (BMP) signaling. Genomic sequencing of BMPR1A in each of these JP kindreds disclosed germline nonsense mutations in all affected kindred members but not in normal control individuals. These findings indicate involvement of an additional gene in the transforming growth factor-β (TGF-β) superfamily in the genesis of JP, and document an unanticipated function for BMP in colonic epithelial growth control.

Factors predictive of survival in ampullary carcinoma.

OBJECTIVE To review the recent Memorial Sloan-Kettering Cancer Center experience with adenocarcinoma of the ampulla of Vater and to identify clinicopathologic factors that have an impact on patient survival. SUMMARY BACKGROUND DATA The prognosis for patients with tumors of the ampulla of Vater is improved relative to other periampullary neoplasms. Identification of independent prognostic factors in ampullary tumors has been limited by small numbers of tumors and a lack of pathologic review. METHODS Data were collected prospectively for patients presenting with periampullary carcinomas to the Memorial Sloan-Kettering Cancer Center between October 15, 1983 and June 30, 1995. The correlation between clinicopathologic variables and survival of ampullary carcinoma was tested by the Kaplan-Meier method and log-rank test, and Cox proportional hazards regression. Survival of patients with periampullary adenocarcinomas was compared by the Kaplan-Meier method. RESULTS In 123 patients presenting with ampullary carcinoma, 101 tumors (82.1%) were resected. Factors significantly correlated with improved survival were resection (p < 0.01), and in resected tumors, negative nodes (p = 0.04) and margins (p = 0.02) independently predicted for improved survival. In periampullary tumors, the highest rates of resection and overall survival (median, 43.6 months) were found in ampullary carcinomas. CONCLUSIONS Factors predictive of improved survival in ampullary carcinoma include resection, negative margins, and negative nodes. Improved overall survival in ampullary relative to periampullary adenocarcinoma is due in part to a significantly higher rate of resection.

The risk of gastrointestinal carcinoma in familial juvenile polyposis

AbstractBackground: Familial juvenile polyposis (JP) is an autosomal dominant condition in which affected individuals develop upper or lower gastrointestinal (GI) juvenile polyps, or both, and have a predisposition to cancer of the gastrointestinal tract. The risk of GI cancer has not been well defined because of the small number of these families and the lack of follow-up. The objective of this study was to determine the prevalence and age at diagnosis of GI polyposis and cancer in a large JP kindred. Methods: Medical records were reviewed, patients were interviewed, and histories were taken. Pathology reports and slides were reviewed by our pathologists. A database was created for analysis of clinical and pathologic factors. Results: This kindred contains 117 members, 29 of whom have had upper or lower GI polyps or cancer, or both. All those affected have had colonic juvenile polyps or cancer, except for two who died of advanced gastric cancer and never had colonic evaluation. Nine individuals have had both upper and lower GI polyps or cancer. Sixteen of 29 (55%) affected patients have developed gastrointestinal cancer. Eleven (38%) have had colon cancer, and six (21%) have had upper GI cancers. Conclusions: The risk of gastrointestinal malignancy in affected members of this JP kindred exceeds 50%. The high risk of GI cancer warrants frequent endoscopic screening of both affected and at-risk family members. Screening will soon be facilitated by presymptomatic genetic testing for the identification of gene carriers.

The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations

Background: Juvenile polyposis (JP) is an autosomal dominant syndrome predisposing to colorectal and gastric cancer. We have identified mutations in two genes causing JP, MADH4 and bone morphogenetic protein receptor 1A (BMPR1A): both are involved in bone morphogenetic protein (BMP) mediated signalling and are members of the TGF-β superfamily. This study determined the prevalence of mutations in MADH4 and BMPR1A, as well as three other BMP/activin pathway candidate genes in a large number of JP patients. Methods: DNA was extracted from the blood of JP patients and used for PCR amplification of each exon of these five genes, using primers flanking each intron–exon boundary. Mutations were determined by comparison to wild type sequences using sequence analysis software. A total of 77 JP cases were sequenced for mutations in the MADH4, BMPR1A, BMPR1B, BMPR2, and/or ACVR1 (activin A receptor) genes. The latter three genes were analysed when MADH4 and BMPR1A sequencing found no mutations. Results: Germline MADH4 mutations were found in 14 cases (18.2%) and BMPR1A mutations in 16 cases (20.8%). No mutations were found in BMPR1B, BMPR2, or ACVR1 in 32 MADH4 and BMPR1A mutation negative cases. Discussion: In the largest series of JP patients reported to date, the prevalence of germline MADH4 and BMPR1A mutations is approximately 20% for each gene. Since mutations were not found in more than half the JP patients, either additional genes predisposing to JP remain to be discovered, or alternate means of inactivation of the two known genes are responsible for these JP cases.

Adenocarcinoma of the small bowel

Small bowel adenocarcinoma (SBA) accounts for 2% of gastrointestinal (GI) tumors and 1% of GI cancer deaths. The objective of this study was to review the National Cancer Data Base (NCDB) to identify case‐mix characteristics, patterns of treatment, and factors influencing survival of patients with SBA.BACKGROUND Small bowel adenocarcinoma (SBA) accounts for 2% of gastrointestinal (GI) tumors and 1% of GI cancer deaths. The objective of this study was to review the National Cancer Data Base (NCDB) to identify case-mix characteristics, patterns of treatment, and factors influencing survival of patients with SBA. METHODS NCDB data from patients diagnosed with primary SBA between 1985-1995 were analyzed. Chi-square statistics were used to compare differences between groups. Disease specific survival (DSS) was calculated using the life table method for patients diagnosed between 1985-1990; univariate differences in survival were compared using the Wilcoxon statistic, and multivariate analyses were performed using a Cox regression model. RESULTS There were 4995 SBA cases reported to the NCDB between 1985-1995, 55% of which occurred in the duodenum, 18% in the jejunum, 13% in the ileum, and 14% in nonspecified sites. The overall 5-year DSS was 30.5%, with a median survival of 19.7 months. By multivariate analysis, factors significantly correlated with DSS included patient age, tumor site, disease stage, and whether cancer-directed surgery was performed. CONCLUSIONS SBA is found most commonly in the duodenum, and patient DSS is reduced at this site compared with those patients with jejunal or ileal tumors. This reduction in survival was associated with a lower percentage of cancer-directed surgery. Patients age > 75 years had a reduced DSS and more duodenal tumors, and were less frequently treated by cancer-directed surgery than their younger counterparts. This study reflects the experience with SBA from a large cross-section of U.S. hospitals, allowing for the identification of prognostic factors and providing a reference with which results from single institutions may be compared.

Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis

BackgroundJuvenile 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 withSMAD4 orBMPR1A mutations (MUT+) compared with those without (MUT-).MethodsDNA was extracted from 54 JP probands and used for polymerase chain reaction of all exons ofSMAD4 andBMPRIA. Products were then sequenced and analyzed for mutations. Medical record data were used to create a JP database, and statistical analysis was performed using Fishers exact and unpairedt-tests.ResultsNine of 54 patients had germlineSMAD4 mutations, 13 hadBMPR1A mutations, and 32 had neither. There were no significant differences betweenSMAD4+ andBMPR1A+ 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).ConclusionsPatients with germlineSMAD4 orBMPR1A mutations have a more prominent JP phenotype than those without, andSMAD4 mutations predispose to UGI polyposis.

A Gene for Familial Juvenile Polyposis Maps to Chromosome 18q21.1

Familial juvenile polyposis (FJP) is a hamartomatouspolyposis syndrome in which affected family members develop upper and lower gastrointestinal juvenile polyps and are at increased risk for gastrointestinal cancer. A genetic locus for FJP has not yet been identified by linkage; therefore, the objective of this study was to perform a focused genome screen in a large family segregating FJP. No evidence for linkage was found with markers near MSH2, MLH1, MCC, APC, HMPS, CDKN2A, JP1, PTEN, KRAS2, TP53, or LKB1. Linkage to FJP was established with several markers from chromosome 18q21.1. The maximum LOD score was 5.00, with marker D18S1099 (recombination fraction of .001). Analysis of critical recombinants places the FJP gene in an 11.9-cM interval bounded by D18S1118 and D18S487, a region that also contains the tumor-suppressor genes DCC and DPC4. These data demonstrate localization of a gene for FJP to chromosome 18q21.1 by linkage, and they raise the possibility that either DCC or DPC4 could be responsible for FJP.

MINIMALLY INVASIVE PARATHYROID SURGERY

More surgeons are performing unilateral exploration for primary hyperparathyroidism (HPT) than ever before. This article reviews the factors that have led to the trend toward less invasive surgery. Discussion includes the history of unilateral exploration for HPT, the advent of magnetic resonance sestamibi imaging, and the development of intraoperative assays for parathyroid hormone. Results of minimally invasive techniques, including radio-guided parathyroidectomy, endoscopic parathyroidectomy, and outpatient parathyroidectomy, also are presented.

HAMARTOMATOUS POLYPOSIS SYNDROMES

Since the histologic description of the hamartomatous polyp in 1957 by Horrilleno and colleagues, descriptions have appeared of several different syndromes with the propensity to develop these polyps in the upper and lower gastrointestinal tracts. These syndromes include juvenile polyposis, Peutz-Jeghers syndrome, hereditary mixed polyposis syndrome, and the phosphatase and tensin homolog gene (PTEN) hamartoma tumor syndromes (Cowden and Bannayan-Riley-Ruvalcaba syndromes), which are autosomal-dominantly inherited, and Cronkhite-Canada syndrome, which is acquired. This article reviews the clinical aspects, the molecular pathogenesis, the affected organ systems, the risks of cancer, and the management of these hamartomatous polyposis syndromes. Although the incidence of these syndromes is low, it is important for clinicians to recognize these disorders to prevent morbidity and mortality in these patients, and to perform presymptomatic testing in patients at risk.

Genetic conditions associated with intestinal juvenile polyps.

Juvenile polyps are hamartomatous polyps found primarily in infants and children, and in association with juvenile polyposis (JP; OMIM# 174900), Cowden syndrome (CS; OMIM# 158350), and Bannayan‐Riley‐Ruvalcaba syndrome (BRRS; OMIM# 153480). Although solitary juvenile polyps are benign lesions, when present in JP patients they may lead to gastrointestinal cancers. Germline mutations in MADH4 and BMPR1A predispose to JP, and both genes are involved in TGF‐β superfamily signaling pathways. In CS and BRRS, juvenile polyps are a less consistent feature, and CS patients are at risk for breast and thyroid cancers. Mutations of the tumor suppressor gene PTEN have been found in the germline of both CS and BRRS patients. Despite different underlying genetic mechanisms, these and other syndromes share the same phenotypic feature of juvenile polyps.