Genomic instability is a classic hallmark of tumorigenesis and tumor progression. It is usually thought of as LOH, loss of heterozygosity, most notably at tumor suppressor loci. However, three papers in this issue highlight other chromosomal alterations that occur as different human cancers progress through their respective clinical stages and outline the significance these alterations might play in molecular diagnostics. Ha et al. (pages 615–617) focus on microsatellite instabilities (MSI), represented by insertion or deletion mutations, in head-and-neck squamous cell cancer (HNSCC.) As might be expected, these simple base pair insertions and deletions are dominant features of solid tumors with significant mismatch repair defects. The molecular progression of HNSCC correlates with the phenotypic spectrum of its dysplasia; there is an increase in the prevalence of LOH as the severity of the dysplasia increases. Ha et al. find that MSI become increasingly more common as early dysplastic legions progress to fully malignant HNSCC, and they conclude that these instabilities are probably acquired during this transition. They therefore claim that microsatellite analysis, which can be performed on genetic samples obtained from saliva and serum, can be a supplemental method for early cancer detection as well as for tumor surveillance. In a similar study, Lerebours et al. (pages 618–622) investigate allelic losses associated with primary inflammatory breast cancer (IBC), a rare but highly metastatic form of breast cancer. In contrast to the case for non-IBC, the molecular mechanisms underlying IBC are poorly understood. This group hypothesized that distinct genetic features might account for the unique clinical and histological aggression exhibited by IBC. They report that LOH is more frequent in IBC than in non-IBC; yet the chromosomal regions where heterozygosity is most frequently lost — 8p, 11q, 16q, and 17p — are the same in both cancer types. Likewise, the oncogenes ERBB2, MYC, and CCND1 are amplified with similar frequencies in both IBC and non-IBC. Hypermethylation of CpG islands in the promoter regions of cancer-causing genes is yet another mechanism of gene silencing utilized in human cancers, including gastric cancer. Intestinal metaplasia (IM) is generally considered to be a preneoplastic lesion of the stomach. To et al. (pages 623–628) analyze the presence of promoter hypermethylation in IM of patients with and without gastric cancer in order to correctly place it chronologically in the multistep progression of gastric carcinogenesis. They report that both the prevalence of promoter hypermethylation and the number of hypermethylated promoters are similar in IM in patients with and without gastric cancer, although the promoters of certain of the genes examined — DAP-kinase, p14Arf, p15Ink4b, and p16CDKN2A — were more frequently hypermethylated in IM cells derived from cancer patients than in those derived from healthy patients. They thus conclude that these epigenetic alterations are already present in the preneoplastic stage, and that they may represent an important pathogenetic mechanism in the development of gastric cancers. Cancer cells are usually not targeted by the immune system because they are not recognized as non-self, and thus they are not recognized as dangerous. Current work seeks to use the vaccine model to alert the immune system to the cancer cells' fatal potential and utilize immune-based therapy to attack the transformed cells. Lin et al. (pages 629–637) chose Listeria monocytogenes, a gram-positive, facultative intracellular bacterium, as a vector to orally deliver human papillomavirus type 16 E7 to syngeneic mice injected with TC-1 or B16F1 tumor cells. L. monocytogenes is an attractive vector because it can present secreted proteins to both the MHC class I and class II pathways and thus can stimulate both CD4+ and CD8+ T-cell responses. They observed that oral vaccination with their recombinant L. monocytogenes causes the regression of tumor growth in syngeneic mice, and they suggest that L. monocytogenes encoding HPV-16 E7 may be a useful oral vaccine to combat cervical cancer. This is a particularly appealing idea because cervical carcinoma remains one of the most common malignancies worldwide, and oral vaccines are easier to administer and less expensive to produce than vaccines formulated for injection. Vidovic et al. (pages 660–664) have attempted to develop an effective vaccine against HER-2 overexpressing tumors, such as those in human breast, lung, prostate, ovarian, colorectal, and endometrial carcinomas, by genetically engineering fusion proteins of HER-2 domains with GM-CSF. HER-2 is an attractive target because its overexpression has been correlated with both poor prognosis and shorter survival times. They found that the most potent antigen consists of the hydrophilic intra- and extracellular regions of HER-2 fused to rat GM-CSF; this antigen is best presented by dendritic cells because it is internalized via GM-CSF cell surface receptors. The soluble antigen is then cocultured with autologous APC to trigger the tumor-specific immune response and suppress tumor growth in vaccinated syngeneic mice injected with HER-2 overexpressing tumor cells. In vivotumor elimination assay.