OBJECTIVES: Germline mutation in adenomatous polyposis coli (APC) is detected in up to 80% of familial adenomatous polyposis (FAP) patients worldwide. In this study, we evaluated clinical features and APC mutations of Singapore FAP patients and contrasted genotype-phenotype correlation with Caucasians from other regions of the world and between FAP patients with and without detectable APC mutations. METHODS: We screened 242 members from 57 unrelated FAP families using a combination of cDNA protein truncation test, multiplex ligation-dependent probe amplification, and differential expression techniques. RESULTS: APC germline mutations were detected in 50 families. In contrast to Caucasians, fundic gland polyposis in Singapore patients was associated with APC mutations throughout the coding region and osteomas were also not confined to codon 767-1573. There was also no FAP-associated hepatoblastoma or medullablastoma. APC mutation-negative patients from four families with mixed (adenomatous/hyperplastic/atypical juvenile) polyps were subsequently reclassified as hereditary mixed polyposis syndrome (HMPS) patients. APC mutation-negative patients with classical adenomatous polyposis were negative for MYH, beta-catenin, and Axin 1 mutations. These patients had a significantly older age at diagnosis (P < 0.001) and more colorectal cancers (P= 0.017) than patients with APC mutations. CONCLUSIONS: We achieved a 94% (50/53) APC mutation detection rate via a combination of techniques, suggesting that the current detection rate is probably not exhaustive. Singapore patients have some features similar to and other features distinct from Caucasians. Furthermore, APC mutation-negative patients have accelerated cancer progression that merits closer surveillance.
OBJECTIVES: Germline mutation in adenomatous polyposis coli (APC) is detected in up to 80% of familial adenomatous polyposis (FAP) patients worldwide. In this study, we evaluated clinical features and APC mutations of Singapore FAPpatients and contrasted genotype-phenotype correlation with Caucasians from other regions of the world and between FAPpatients with and without detectable APC mutations. METHODS: We screened 242 members from 57 unrelated FAP families using a combination of cDNA protein truncation test, multiplex ligation-dependent probe amplification, and differential expression techniques. RESULTS:APC germline mutations were detected in 50 families. In contrast to Caucasians, fundic gland polyposis in Singapore patients was associated with APC mutations throughout the coding region and osteomas were also not confined to codon 767-1573. There was also no FAP-associated hepatoblastoma or medullablastoma. APC mutation-negative patients from four families with mixed (adenomatous/hyperplastic/atypical juvenile) polyps were subsequently reclassified as hereditary mixed polyposis syndrome (HMPS) patients. APC mutation-negative patients with classical adenomatous polyposis were negative for MYH, beta-catenin, and Axin 1 mutations. These patients had a significantly older age at diagnosis (P < 0.001) and more colorectal cancers (P= 0.017) than patients with APC mutations. CONCLUSIONS: We achieved a 94% (50/53) APC mutation detection rate via a combination of techniques, suggesting that the current detection rate is probably not exhaustive. Singapore patients have some features similar to and other features distinct from Caucasians. Furthermore, APC mutation-negative patients have accelerated cancer progression that merits closer surveillance.
Authors: Jun Li; Susan L Woods; Sue Healey; Jonathan Beesley; Xiaoqing Chen; Jason S Lee; Haran Sivakumaran; Nicci Wayte; Katia Nones; Joshua J Waterfall; John Pearson; Anne-Marie Patch; Janine Senz; Manuel A Ferreira; Pardeep Kaurah; Robertson Mackenzie; Alireza Heravi-Moussavi; Samantha Hansford; Tamsin R M Lannagan; Amanda B Spurdle; Peter T Simpson; Leonard da Silva; Sunil R Lakhani; Andrew D Clouston; Mark Bettington; Florian Grimpen; Rita A Busuttil; Natasha Di Costanzo; Alex Boussioutas; Marie Jeanjean; George Chong; Aurélie Fabre; Sylviane Olschwang; Geoffrey J Faulkner; Evangelos Bellos; Lachlan Coin; Kevin Rioux; Oliver F Bathe; Xiaogang Wen; Hilary C Martin; Deborah W Neklason; Sean R Davis; Robert L Walker; Kathleen A Calzone; Itzhak Avital; Theo Heller; Christopher Koh; Marbin Pineda; Udo Rudloff; Martha Quezado; Pavel N Pichurin; Peter J Hulick; Scott M Weissman; Anna Newlin; Wendy S Rubinstein; Jone E Sampson; Kelly Hamman; David Goldgar; Nicola Poplawski; Kerry Phillips; Lyn Schofield; Jacqueline Armstrong; Cathy Kiraly-Borri; Graeme K Suthers; David G Huntsman; William D Foulkes; Fatima Carneiro; Noralane M Lindor; Stacey L Edwards; Juliet D French; Nicola Waddell; Paul S Meltzer; Daniel L Worthley; Kasmintan A Schrader; Georgia Chenevix-Trench Journal: Am J Hum Genet Date: 2016-04-14 Impact factor: 11.025
Authors: Thérèse M F Tuohy; Michelle W Done; Michelle S Lewandowski; Patricia M Shires; Devki S Saraiya; Sherry C Huang; Deborah W Neklason; Randall W Burt Journal: Hum Genet Date: 2009-12-22 Impact factor: 4.132
Authors: Frederik J Hes; Dina Ruano; Marry Nieuwenhuis; Carli M Tops; Melanie Schrumpf; Maartje Nielsen; Petra E A Huijts; Juul T Wijnen; Anja Wagner; Encarna B Gómez García; Rolf H Sijmons; Fred H Menko; Tom G W Letteboer; Nicoline Hoogerbrugge; Jan Harryvan; Ellen Kampman; Hans Morreau; Hans F A Vasen; Tom van Wezel Journal: J Med Genet Date: 2013-11-19 Impact factor: 6.318