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View the Table of Contents for the October 15 issue of Cancer Research.
Goldstein et al. Page 9818
The GenoMEL consortium, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia, has created the largest set of familial melanoma samples yet available. These were used to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/ARF, that encodes p16 and p14ARF, and CDK4, and to evaluate their relationship with pancreatic cancer, neural system tumors, and uveal melanoma. Overall, Goldstein et al. found that 41% of families had mutations; most involved p16. Mutations in CDK4 and ARF occurred at similarly low frequencies (2-3%). The frequencies and types of CDKN2A mutations differed by geographic locale. Further, the proportion of families with the most common CDKN2A founder mutations from each locale varied across the regions. This GenoMEL study provides an extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available.
Muñoz et al. Page 9837
The TGF-β signaling pathway is a tumor suppressor pathway that is commonly inactivated in colon cancer. TGF-β is a secreted ligand that mediates its effects through a transmembrane heteromeric receptor complex, which consists of type I (TGFBR1) and type II (TGFBR2) subunits. In order to assess the functional role of TGFBR2 inactivation in the multistep progression sequence of colon cancer, Muñoz et al. generated a mouse model that recapitulates two common genetic events observed in human colon cancer. The results showed that a loss of TGFBR2 in intestinal epithelial cells promotes the invasion and malignant transformation of tumors initiated by the Apc mutation, providing evidence that Wnt signaling deregulation and TGF-β signaling inactivation cooperate to drive the initiation and progression, respectively, of intestinal cancers in vivo.
McLachlan et al. Page 9886
The connexins and Cx26 and Cx43 are gap junction proteins and are often down-regulated in breast cancer. McLachlan et al. reported that overexpression of Cx26 or Cx43 has tumor-suppressive properties in a 3D model of breast differentiation. They reduced anchorage-independent cell growth and induced partial redifferentiation of 3D organoids of MDA-MB-231 cells. The majority of exogenous connexins did not localize to the cell-cell interface or rescue gap junctional intercellular communication (GJIC) as assessed by dye transfer, providing evidence of a GJIC-independent mechanism of mammary tumor suppression. The authors concluded that Cx26 and Cx43 inhibit the malignant properties of MDA-MB-231 cells via GJIC-independent mechanisms including regulation of EMT and angiogenesis.
Page 10205
Chromosome 22q12.3 is one of the most promising regions for familial prostate cancer gene identification; with linkage evidence ranging from LOD=1.50 to LOD=3.57 in nine independent studies. Using 14 high-risk prostate cancer Utah pedigrees, Camp et al. localized the most likely region harboring the gene to an 880 kb interval at chromosome 22q12.3. This is the smallest currently defined linkage region of any prostate cancer predisposition locus. These findings are of significance not only to the prostate cancer genetics field, but also to other linkage studies, as they indicate a recombinant mapping method using extended pedigrees that shows great promise for localizing genes involved in common disease.
Page 10213
Sun exposure and higher vitamin D intake have been associated with lower death rates for pancreatic cancer. 25-hydroxyvitamin D[25(OH)D] is the major circulating vitamin D metabolite and is also considered the best indicator of vitamin D status. Stolzenberg-Solomon et al. conducted a nested case-control study to test whether more adequate vitamin D status was associated with lower pancreatic cancer risk in male smokers. Contrary to expectations, subjects with higher vitamin D status had a significant three-fold increased pancreatic cancer risk compared to those with lower vitamin D status. The authors' findings need to be replicated in other populations and caution is warranted in their interpretation; however, they provide clues that further the understanding of the etiology of this highly fatal cancer.