RECIPROCAL RELATIONSHIP BETWEEN THE TUMOR SUPPRESSORS P53 AND BAX IN PRIMARY COLORECTAL CANCERS

Though most colorectal cancers show allelic losses, a subset of colore ctal cancers (microsatellite instability or MSI-positive cancers) deve lop numerous small insertion and deletion mutations in repetitive DNA, Some of these sequences occur in coding regions of cancer related gen es which, when targeted by frameshift mutations, produce truncations i n their protein product, Such a gene is the proapoptotic tumor suppres sor, BAX, mutated by frameshifts within a polyG sequence in approximat ely 50% of MSI-positive colorectal cancers. BAX is directly transactiv ated by p53, a gene commonly mutated in colorectal cancers but not oft en in MSI-positive lesions. Here we sought to characterize the relatio nship between BAX and p53 by simultaneously analysing a selected serie s of 65 colorectal tumors for mutations in the entire coding regions o f both genes. The tumors comprised 19 MSI-high, 12 MSI-low and 34 MSI- null cancers. Eight of 19 MSI-high sporadic colorectal cancers (42%) c ontained insertions and deletions at the polyG tract in the BAX gene, In addition, three somatic BAX missense mutations were identified in t wo tumors. A single missense mutation was detected in an MSI-high tumo r that also contained a frameshift microdeletion, and two missense mut ations were identified in an MSI-null tumor wild-type for p53, p53 mut ations were detected in 5/12 MSI-low tumors (42%) and 12/34 MSI-null t umors (35%), Of significance, no p53 mutations were detected in MSI-hi gh tumors. This study demonstrates that a reciprocal relationship exis ts between p53 and BAX in sporadic colorectal cancers, and further sup ports the hypothesis that MSI-low tumors are biologically similar to M SI-null tumors.