ORIGINAL CONTRIBUTION Implication of Adenomatous Polyposis Coli and MUTYH Mutations in Familial Colorectal Polyposis Marina De Rosa, Ph.D. 1 & Martina Galatola, B.S. 1 & Santa Borriello, B.S. 1 Francesca Duraturo, Ph.D. 1 & Stefania Masone, M.D. 2 & Paola Izzo, Ph.D. 1 1 Dipartimento di Biochimica e Biotecnologie Mediche and CEINGE Biotecnologie Avanzate, Universit( di Napoli Federico II, Napoli, Italy 2 Dipartimento Assistenziale di Chirurgia Generale e Geriatria, Endoscopia Diagnostica e Operativa, Universit( di Napoli Federico II, Napoli, Italy PURPOSE: Familial adenomatous polyposis is an autosomal dominantly inherited syndrome characterized by hundreds or thousands of colorectal polyps and a high risk of colorectal cancer at a young age. Truncating germline mutations in the adenomatous polyposis coli gene are detected in approximately 80 percent of patients with classical familial adenomatous polyposis and in approximately 10 percent of the attenuated familial adenomatous polyposis patients. METHODS: We investigated the adenomatous polyposis coli and MUTYH genes mutations in a well-characterized series of 25 unrelated Italian patients with familial adenomatous polyposis. RESULTS: We characterized the specific adenomatous polyposis coli gene mutation in 10 probands, and identified eight truncating mutations (4 novel and 4 known mutations) and two splicing mutations. One of these, a novel missense mutation in exon 15, activates an exonic splicing enhancer control sequence. Moreover, 11 MUTYH gene mutations have been identified in 7 patients without a dominant family history of polyposis. CONCLUSIONS: This study enlarges the genotype-phenotype correlations of familial adenomatous polyposis and suggests that messenger alterations could be responsible for a subset of familial adenomatous polyposis cases without germ-line adenomatous polyposis coli or MUTYH gene mutations. It also confirms that genotype-phenotype correlations in MUTYH-associated polyposis are very complex. KEY WORDS: Adenomatous polyposis coli gene; Familial adenomatous polyposis; MUTYH: Human homolog of E. Coli MutY gene. F amilial adenomatous polyposis (FAP) is an inherited autosomal dominant precancerous condition char- acterized by multiple adenomatous polyps in the colon and rectum. If not treated, these polyps invariably develop to colorectal cancer, typically by the age of 40 years. 1 This condition is primarily associated with germ- line mutations in the adenomatous polyposis coli (APC) gene (OMIM*175100), 2,3 an ubiquitously expressed tu- mor suppressor, which contains at least 21 exons. 4 The clinical manifestations and severity of FAP vary greatly with the mutation site. The disorder is classically characterized by more than 100 colorectal adenomas, early onset of colorectal carcinoma, and specific extracolonic features. 5 Attenuated familial adenomatous polyposis (AFAP) is a milder form of the disease in which patients have fewer than 100 adenomas. AFAP patients with dominant inheritance harbor germ-line mutations in the 5¶ or 3¶ regions of the APC gene or in regions affected by alternative splicing events. 6Y9 Another group of patients have the FAP or AFAP phenotype and recessive inheritance. These patients often harbor inherited biallelic mutations in the base-excision repair (BER) gene MYH (MUTYH; OMIM# 604933, Gene Bank NM_012222.1). 10,11 Finally, a group of individuals have an AFAP-like phenotype, with 3 to 100 polyps throughout the colo- rectum and often with unclear or no family history of polyposis. In most cases, no germ-line APC or MYH mutations have been detected in these patients. By using a combination of the polymerase chain reaction (PCR), reverse transcriptase (RT)-PCR, protein truncation test (PTT), single-strand conformation polymorphism 268 DISEASES OF THE COLON &RECTUM VOLUME 52: 2 (2009) Supported by grants from MIUR (PRIN 2004), Regione Campania (L.R.N.5, 2005), and Ricerca Oncologica RF-CAM-2006Y353005. Address of correspondence: Paola Izzo, Ph.D., Dipartimento di Biochimica e Biotecnologie Mediche and CEINGE Biotecnologie- Avanzate, Universit( di Napoli Federico II, via S. Pansini 5, 80131 Napoli, Italy. E-mail: izzo@dbbm.unina.it Dis Colon Rectum 2009; 52: 268Y274 DOI: 10.1007/DCR.0b013e318197d15c BThe ASCRS 2009 Copyright @ The ASCRS 2009. Unauthorized reproduction of this article is prohibited.