Prevalence of Germline PTEN, BMPR1A, SMAD4, STK11, and ENG Mutations in Patients With Moderate-Load Colorectal Polyps

Abstract

BACKGROUND & AIMS Gastrointestinal polyposis is a common clinical problem, yet there is no consensus on how to best manage patients with moderate-load polyposis. Identifying genetic features of this disorder could improve management, and especially surveillance, of these patients. We sought to determine the prevalence of hamartomatous polyposis associated mutations in the susceptibility genes PTEN, BMPR1A, SMAD4, ENG, and STK11 in individuals with 5 or more gastrointestinal polyps, including at least 1 hamartomatous or hyperplastic/serrated polyp. METHODS We performed a prospective, referral-based study of 603 patients (median age 51 y; range, 2–89 y), enrolled from June 2006 through January 2012. Genomic DNA was extracted from peripheral lymphocytes and analyzed for specific mutations and large rearrangements in PTEN, BMPR1A, SMAD4, and STK11, as well as mutations in ENG. Recursive partitioning analysis was used to determine cutoffs for continuous variables. The prevalence of mutations was compared using Fischer’s exact test. Logistic regression analyses were used to determine univariate and multivariate risk factors. RESULTS Of 603 patients, 119 (20%) had a personal history of colorectal cancer and most (461; 76%) had fewer than 30 polyps. Seventy-seven patients (13%) were found to have polyposis-associated mutations, comprising 11 in ENG (1.8%), 13 in PTEN (2.2%), 13 in STK11 (2.2%), 20 in BMPR1A (3.3%), and 21 in SMAD4 (3.5%). Univariate clinical predictors for risk of having these mutations included age at presentation less than 40 years (19% vs 10%; P=.008), a polyp burden of 30 or more (19% vs 11%; P=0.014), and male sex (16% vs 10%; P=.03). Patients who had 1 or more ganglioneuromas (29% vs 2%; P<.001) or presented with polyps of 3 or more histologic types (20% vs 2%; P=.003) were more likely to have germline mutations in PTEN. CONCLUSIONS Age less than 40 years, male sex, and specific polyp histologies are significantly associated with risk of germline mutations in hamartomatous-polyposis associated genes. These associations could guide clinical decision making and further investigations.

PTEN Hamartoma Tumour Syndrome:Gastrointestinal Manifestations ofTwo Cases Diagnosed in Singapore

“…There are varied gastrointestinal manifestations of PHTS as detailed in Table 1 [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17], of which upper and lower gastrointestinal tract (GIT) polyposis is most common. PHTS patients are reported to have a wide spectrum of polyp histologies throughout their upper and lower GIT [3,4], with many having more than a single histology [5].…”

“…Gastrointestinal polyposis [2][3][4][5][6][7][8][9][10][11][12] Glycogenic acanthosis [2,8,11,13] Intestinal hyperplasia 14…”

The growing complexity of the intestinal polyposis syndromes

“…Histologically, there may be confusion with juvenile polyps [Jass, 2008]. Stromal ganglion cells are seen frequently [Jass, 2008], and may be so abundant that the appearance is that of ganglioneuromas [Trufant et al, 2012;Ngeow et al, 2013;Ponz de Leon et al, 2013], but lesions in which autonomic nerves are predominant, giving a ganglioneuroma-like appearance seem to be exceptional . Instead, true intestinal ganglioneuromas are found in neurofibromatosis type 1 and multiple endocrine neoplasia type 1 [Ledwidge et al, 2007].…”

“…Simultaneous occurrence of polyps of different histologies (including at least three of the following subtypes: adenoma, hamartoma, lipoma, ganglioneuroma-like, juvenile, and inflammatory polyps) has been found to be specifically associated with presence of PTEN mutations in a series of patients with multiple polyposis [Ngeow et al, 2013]. The number of polyps can range from none to innumerable, while their incidence is unknown; in a recent study 95% of in PTEN mutation carriers subjected to colonoscopy were found to have intestinal polyps [Heald et al, 2010].…”

“…Mutations of BMPR1A, SMAD4, ENG, PTEN, or STK11 were found in 13%. Mutation positive patients were more likely to be diagnosed <40 years and to have !30 polyps [Ngeow et al, 2013]. To further complicate the matter, some patients with Lynch syndrome may present with a multiple adenoma phenotype, occasionally mimicking AFAP or MAP [Cao et al, 2002].…”