4q27

HSMAD2,MAD2

Like other solid tumors, ovarian cancers, especially those at later stages, demonstrate significant aneuploidy and multiple regions of chromosome loss and amplification. MAD2L1 maps to 4q27, an area that is unstable in several cancers as revealed by loss of heterozygosity and comparative genomic hybridization studies. Interestingly, some of the malignant tumors in individuals with BRCA1 germline mutations have somatic loss of chromosome 4q, suggesting that alterations of genes in this region may be associated with breast cancer

No cytogenetic translocations involving this gene, however, have been reported or have been associated with any disease, including cancer

None described

Work by several groups have now suggested that dysfunction of MAD2A may lead to malignancy or degeneration of normal cells, but compelling evidence that supports a role for MAD2L1 alterations in human cancers are still lacking. Despite this lack of solid data, there is increasing suggestive evidence to implicate MAD2L1 alterations in association with the development and/or progression of human cancer. First, aneuploidy is a commonly observed phenotype in many solid tumor malignancies, especially in later stage tumors. Chromosomal instability (CIN) correlates with aneuploidy and is thought to contribute to genetic instability. Thus, it is widely hypothesized that genomic instability which leads to aneuploidy may accelerate malignant progression in many solid tumor malignancies. Mutations in the genes controlling the mitotic checkpoint, including MAD2L1, have therefore been implicated to contribute to CIN in the pathogenesis of solid tumor malignancies. By monitoring proper microtubule assembly and attachment at the kinetochore, the mitotic checkpoint genes regulate the cell cycle to ensure accurate chromosome alignment and segregation at anaphase to generate euploid daughter cells. Loss of appropriate chromosome attachments at the kinetochore or defects in the mitotic spindle lead to cell cycle arrest and a block in the initiation of anaphase. Mad2 is just one member of a handful of yeast genes, the budding uninhibited by benomyl BUB and mitotic arrest deficient (MAD) families of genes, that are important regulators of this mitotic spindle checkpoint. Studies in colorectal cell lines suggest that dominant negative mutations in the human ortholog BUB1 may have a role in CIN and aneuploidy led to speculation about the potential role of MAD2L1 in human cancers. However, no MAD2L1 mutations were identified in colon cancer cells. Human breast tumor cell line T47D has reduced MAD2 expression and it fails to arrest in mitosis after nocodazole treatment. That loss of MAD2 function might also lead to aberrant chromosome segregation in mammalian cells was suggested. A truncation mutation in MAD2L1 in breast cancer with altered protein expression was subsequently reported but no functional studies have yet demonstrated a functional role in oncogenesis has been demonstrated. Studies of Brca2 deficient murine cells further supported a putative role for these genes in cancer as Bub1 mutations were demonstrated to potentiate growth and cellular transformation (Lee et al., 1999). Secondly, the studies of Mad2 knockout mice have demonstrated that embryonic cells lacking Mad2 fail to arrest in response to microtubule inhibitors and that loss of the checkpoint results in chromosome missegregation and apoptosis. It has subsequently been reported that deletion of one allele results in a defective mitotic checkpoint in both human cancer cells and murine primary embryonic fibroblasts. Checkpoint-defective cells show premature sister chromatid separation in the presence of spindle inhibitors and an elevated rate of chromosome missegregation events in the absence of these agents. Furthermore, Mad2 +/- mice develop lung tumors at high rates after long latencies, implicating defects in the mitotic checkpoint in tumorigenesis.