The idea that common epithelial cancers evolve from dysplasia or carcinoma in situ has been challenged by the discovery of occult disease in normal-appearing cells, known as the field effect, which interests areas that might form large plaques in the mucosal membrane. Forerunner (FR) genes, which map to genomic regions close to established tumour-suppressor genes, seem to have a role in this process, as inactivation of FR genes precedes the functional loss of the close tumour suppressors.

In a new study published in Cell Reports, the authors developed an innovative whole-organ mapping method that, in combination with genomic markers, can help dissect the sequence of events of initial clonal expansion of a preneoplastic clone. This strategy was used to identify FR genes in the region around the tumour suppressor RB1. A minimal segment of 1.7 Mb whose loss of polymorphisms was associated with early clonal expansion of a preneoplastic clone was identified and included 20 putative candidate genes. Expression studies on a 5-Mb segment around RB1 enabled the identification of five FR genes whose expression was downregulated by at least twofold in >50% of the samples: ITM2B, LPAR6, MLNR, CAB39L and ARL11. Hypermethylation was identified as the primary mechanism of silencing of these genes.