HPP1: a transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers

Young J, Biden KG, Simms LA, Huggard P, Karamatic R, Eyre HJ, Sutherland GR, Herath N, Barker M, Anderson GJ, Fitzpatrick DR, Ramm GA, Jass JR, Leggett BA (2001) HPP1: a transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers. Proceedings of the National Academy of Sciences of the United States of America 98:265-270

Adenomas are the precursors of most colorectal cancers. Hyperplastic polyps have been linked to the subset of colorectal cancers showing DNA microsatellite instability, but little is known of their underlying genetic etiology. Using a strategy that isolates differentially methylated sequences from hyperplastic polyps and normal mucosa, we identified a 370-bp sequence containing the 5' untranslated region and the first exon of a gene that we have called HPP1. Rapid amplification of cDNA ends was used to isolate HPP1 from normal mucosa. Using reverse transcription-PCR, HPP1 was expressed in 28 of 30 (93%) normal colonic samples but in only seven of 30 (23%) colorectal cancers (P < 0.001).="" the="" 5'="" region="" of="" hpp1="" included="" a="" cpg="" island="" containing="" 49="" cpg="" sites,="" of="" which="" 96%="" were="" found="" to="" be="" methylated="" by="" bisulfite="" sequencing="" of="" dna="" from="" colonic="" tumor="" samples.="" by="" cobra="" analysis,="" methylation="" was="" detected="" in="" six="" of="" nine="" (66%)="" adenomas,="" 17="" of="" 27="" (63%)="" hyperplastic="" polyps,="" and="" 46="" of="" 55="" (84%)="" colorectal="" cancers.="" there="" was="" an="" inverse="" relationship="" between="" methylation="" level="" and="" mrna="" expression="" in="" cancers="" (r="-0.67;" p="">< 0.001),="" and="" 5-aza-2-deoxycytidine="" treatment="" restored="" hpp1="" expression="" in="" two="" colorectal="" cancer="" cell="" lines.="" in="" situ="" hybridization="" of="" hpp1="" indicated="" that="" expression="" occurs="" in="" epithelial="" and="" stromal="" elements="" in="" normal="" mucosa="" but="" is="" silenced="" in="" both="" cell="" types="" in="" early="" colonic="" neoplasia.="" hpp1="" is="" predicted="" to="" encode="" a="" transmembrane="" protein="" containing="" follistatin="" and="" epidermal="" growth="" factor-like="" domains.="" silencing="" of="" hpp1="" by="" methylation="" may="" increase="" the="" probability="" of="" neoplastic="">