Signal Transduction

N. Rampino, H. Yamamoto, Y. Ionov, Y. Li, H. Sawai, J.C. Reed, M. Perucho, "Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype," Science, 275:967-9, Feb. 14, 1997. (Cited in more than 218 papers since publication) Comments by Manuel Perucho, director of the oncogene and tumor suppressor gene program at the Burnham Institute, La Jolla, Calif., and Nicholas Rampino, associate professor at the Burnham Institute Manuel Perucho Though healthy cells divide with high fidelity, mutations are the hallmark of cancer cells. This may explain the boundless capability of cancer cells to continually grow and evade the stopgaps of human defenses. The mutator phenotype hypothesis attributes this phenomenon to an increasing rate of errors in DNA replication as a tumor grows.1 According to this theory genes encoding proteins such as DNA polymerases and DNA repair enzymes, molecules that play an important role in replication, may be mutated in cancer cells. In consequence, other genes responsible for maintaining the stability of the genome and the control of proliferation may become mutated also. Manuel Perucho's lab found the first evidence supporting the mutator phenotype hypothesis in a subgroup of colon tumors, including those from patients with hereditary nonpolyposis colorectal cancer (HNPCC).2 The majority of HNPCC tumor cells exhibit variations in the length of microsatellite sequences, short repetitive nucleotide sequences in DNA such as a repeat of eight adenines. These repetitive sequences are copied less accurately than nonrepetitive sequences, and this often results in addition or deletion of a nucleotide base. In normal people, mutations in microsatellites are corrected by the DNA mismatch repair system. The human genome contains an enormous number of these microsatellites, so a mutator phenotype can cause more than 100,000 mutations in these sequences alone.3 Nicholas Rampino and Perucho became interested in finding the specific genes that are targets for the mutator phenotype. They postulated that the microsatellite instability due to inactivation of mismatch repair genes is not making the cells grow any faster or giving them neoplastic properties. "We started looking for cancer genes propelling the tumorigenesis process as a consequence of the mutator activity of the mutated mismatch repair genes," says Perucho. The BAX gene was one of several candidates containing repetitive sequences in their coding regions. The group studied human colon cancer cells for mutations in an eight-guanine tract of BAX. They found half of the colon tumors that exhibited the mutator phenotype had frameshift mutations caused by either a guanine addition or deletion. "We believe this is a completely different type of tumor that follows a mutator pathway, which is different from the suppressor pathway," comments Perucho. The frameshift mutation inactivates BAX. Thus, cells lacking the BAX protein may not be able to trigger apoptosis after receiving the suicide signal. "If BAX is not functioning, the cell may have more time and leeway to become cancerous," Rampino comments. Perucho feels this paper is highly cited because the findings affect two large groups: apoptosis researchers and researchers working on the molecular genetics of cancer. He adds, "This is the first clear example of a mutated apoptotic gene found in a significant number of tumors." In colon and gastric cancers of the mutator phenotype, the incidence of BAX mutation is nearly 75 percent. Perucho has gone on to find another hot spot in BAX at codon 169: a missense mutation that results in an amino acid substitution.4 A methionine or alanine substitutes for the wild-type serine in several different tumors. "In a recent paper5 we show that indeed this missense mutation at codon 169 is functional, because it decreases the proapoptotic activity of the gene product," explains Perucho. His group has collected unpublished evidence that the frameshift mutations in the BAX gene are functional also, since there is a strong selection for these mutations in vivo during tumorigenesis. The loss of the wild-type BAX allele provides some survival advantage to the tumor cell. The role of the mutations induced by the mutator phenotype and their importance in human cancer are still not well understood. Rampino is studying the flanking sequences around different microsatellites to determine whether they make DNA susceptible to mutations. "Different people have slight variations in their DNA sequence. This may be why some people are more prone to cancer than others," theorizes Rampino. Understanding the molecular mechanisms that underlie the tumorigenesis process, particularly the etiology of the mutations, will be critical in treating cancer. Perucho hopes this research will help answer the question: "What causes all these genes to be mutated and eventually lead to cancer?" References 1. L.A. Loeb et al., "Errors in DNA replication as a basis of malignant change," Cancer Research, 34:2311-21, 1974. 2. M.A. Peinado et al., "Isolation and characterization of allelic loss and gains in colorectal tumors by arbitrarily primed polymerase chain reaction," Proceedings of the National Academy of Sciences, 89:10065-9,1992. 3. Y. Ionov et al., "Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis," Nature, 363:558-61, 1993. 4. H. Yamamoto et al., "Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype," Cancer Research, 57:4420-6, 1997. 5. J. Gil et al., "Impairment of the proapoptotic activity of Bax by missense mutations found in gastrointestinal cancers," Cancer Research, 59:2034-7, May 1, 1999.

Signal Transduction

Interested in reading more?

Become a Member of