Diagnostic Accuracy of a Panel of Bacterial Gene Markers (M3) for Colorectal Advanced Neoplasia

Colorectal cancer (CRC) is the one of the most common cancers in Hong Kong with more than 5,500 new cases annually. There is prevailing evidence of increasing trend of young onset CRC globally. Early detection and resection of pre-malignant colorectal neoplasia has shown to reduce CRC-related mortality. Non-invasive stool tests including guaiac-based faecal occult blood tests (gFOBT) and faecal immunochemical tests (FIT) are the cornerstones of population-based CRC screening programmes. The major limitation of this widely used strategy is its unsatisfactory sensitivities for CRC (79%) and advanced adenomas (AA; 40%). The sensitivity for non-advanced adenomas is even lower than 10%. A large proportion of advanced and non-advanced adenomas will be missed by FIT alone. Therefore, identification of alternative non-invasive test with better sensitivity to detect colorectal neoplasia is warranted. Multitarget stool DNA test and faecal microbial DNA markers appear to be promising options for CRC screening. Several bacterial gene markers have been identified by metagenome sequencing and reported to be associated with CRC, including Fusobacterium nucleatum (Fn), Clostridium hathewayi (Ch) and Bacteroides clarus (Bc). However, these molecular markers had low accuracy in distinguishing adenomas from normal tissue. Recently, a new Lachnoclostridium gene marker (labelled as 'm3') has been shown to have high diagnostic yield for the detection of colorectal adenomas. In a case-control study of 1012 subjects, a linear increasing trend of m3 level was observed from fecal samples of healthy subjects to those with adenomas and cancers. The overall sensitivity of m3 was significantly higher than FIT in detecting all adenomas (48% vs 9.3%), AA (50.8% vs 16.1%) and non-advanced adenomas (44.2% vs 0%). The diagnostic accuracy of m3 could be further enhanced by combining with a panel of fecal microbial markers composing of Fusobacterium nucleatum (Fn), Bacteroides clarus (Bc), Clostridium hathewayi (Ch) for CRC (82.3%) and adenomas (64.2%). We hypothesized that the combination of these 4 bacterial gene markers (known as M3) is more sensitive than FIT in detecting colorectal advanced neoplasia.