Germ-line Mutation Associated with Multi-Nodular Goiter and Papillary Thyroid Cancer
A germ-line mutation in the gene that encodes thyroid transcription factor-1 (TTF-1) may be associated with multi-nodular goiter (MNG) and with progression to papillary thyroid cancer (PTC).
It is known that some patients who have MNG progress to PTC, but a genetic link between the two diseases was not known. TTF-1 is known to be involved in thyroid development and is expressed at a lower level in malignant thyroid tissue than normal tissue.
In the current study, Elly S. W. Ngan, Ph.D., of the University of Hong Kong, and colleagues examined the gene that encodes TTF-1, called TITF-1/NKX2.1, in three groups of people: 20 individuals with MNG that progressed to PTC; 284 PTC patients with no history of MNG; and 349 healthy individuals.
Four of the 20 MNG/PTC patients carried a single point mutation in the TITF-1/NKX2.1 gene, including two individuals with a family history of MNG. Introduction of the mutant gene into cells grown in vitro increased their proliferation rate and increased expression of genes associated with cancer cell growth.
"Our findings may be relevant to the search for molecular markers to assess risk for MNG/PTC, through regular screening of relatives of PTC patients affected with MNG," the authors conclude.
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Early Mammograms May Have Net Harm in Some BRCA Mutation Carriers
The risk of radiation-induced breast cancer may outweigh the benefits of mammography in women under the age of 30 who carry a mutation in BRCA1 or BRCA2, according to a mathematical modeling study.
The general recommendation for women who carry a mutation in BRCA1/2 is to start getting annual mammograms as early as 25 to 30 years of age. However, it is not clear whether the risk of radiation-induced breast cancer would limit the benefit of early mammography.
To estimate the impact of early mammograms on overall breast cancer risk, Amy Berrington de Gonzalez, D.Phil., of the Johns Hopkins Bloomberg School of Public Health in Baltimore, and colleagues modeled excess breast cancer mortality following five annual mammograms starting at various ages.
The model indicated that women who underwent five mammograms between the ages of 24 and 29 would have an additional 26 breast cancers per 10,000 women due to the radiation. Between the ages of 30 and 34 they would have an excess of 20 additional cancers, and between 35 and 39 an additional 13 cancers. To outweigh these risks, mammography screening would have to reduce breast cancer mortality by 51 percent for women between the ages of 24 and 29, by 12 percent for those between 30 and 34, and by 4 percent for those between 30 and 34. The investigators conclude that if their assumptions are correct and mammograms reduce breast cancer mortality by 15-25 percent, which is consistent with empirical data, then there there would be no benefit for mammograms in women under the age of 30 and a marginal benefit for women between the ages of 30 and 34.
"In the absence of direct empiric data, our estimates can be used by those involved in the decision-making process for BRCA mutation carriers to assess whether the benefits from early mammographic screening are likely to outweigh the radiation risks," the authors conclude.
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Benzyl Isothiocyanate Induces Apoptosis in Pancreatic Cancer Cells
Benzyl isothiocyanate (BITC), a compound found in cruciferous vegetables, induces apoptosis in human pancreatic cancer cells via a mechanism dependent on the protein STAT-3.
BITC has been reported to have anticancer activity, but the mechanism by which it works is unknown. In the current study, Ravi P. Sahu, Ph.D., and Sanjay K. Srivastava, Ph.D., of the Texas Tech University Health Sciences Center in Amarillo, examined the effects of BITC on pancreatic cancer cell lines grown in culture and on a mouse model of pancreatic cancer.
The investigators found that BITC increased cell death by reducing the amount of activated STAT-3 protein, which promotes survival and proliferation in cancer cells. Overexpression of STAT-3 in cultured cells eliminated the effect of BITC. The viability of normal pancreatic cells was not affected by BITC treatment. Tumors grew more slowly in mice treated with BITC than in animals treated with vehicle alone.
"Taken together, these findings may provide the basis for further preclinical and clinical investigation of BITC for the chemoprevention and/or chemotherapy of pancreatic cancer," the authors conclude.
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Molecular Studies Explain Imatinib-Resistance Mutations
Molecular modeling and in vitro studies may explain why one particular mutation is frequently seen in patients whose tumors become resistant to imatinib.
Patients with gastrointestinal stromal tumor, chronic myeloid leukemia, and idiopathic hypereosinophilic syndrome can develop resistance to imatinib. Resistance is often associated with second-site mutations in the ATP-binding pocket of the three tyrosine kinases affected by these diseases, KIT, BCR-ABL, and PDGFRA, respectively.
To learn why a second-site mutation consistently changes a threonine to an isoleucine in each of the three affected tyrosine kinases, Elena Tamborini, of the Fondazione IRCCS Istituto Nazionale dei Tumori Milano in Italy, and colleagues modified KIT genes that would make proteins with all possible substitutions of the threonine at position 670 and introduced these mutant genes into cells. The researchers also modeled the relative affinity of ATP and imatinib for the mutant proteins using computer simulations.
Only cells that expressed an isoleucine-substituted KIT protein were able to grow in the presence of imatinib in vitro. Modeling showed that only the KIT with an isoleucine substitution had both a high enough affinity for ATP to promote cell growth and a low enough affinity for imatinib to be resistant to treatment.
"We believe that this study demonstrates that computer-based molecular simulation is a reliable technique that is able to predict in vitro interactions between tyrosine kinases and their natural ligands and inhibitors," the authors write. "Accordingly, an in silico approach could be used to predict the biological response to new molecules conceived as small-molecule inhibitors of tyrosine kinases in the future."
Contact: Elena Tamborini, Elena.Tamborini@istitutotumori.mi.it., +39 02 2390 2280
Also in the January 27 JNCI:
|Contact: Caroline McNeil|
Journal of the National Cancer Institute