A new paper by Kerstin Meyer and colleagues, published this week in the open-access journal PLoS Biology, shows how specific changes in the FGFR2 gene alter the way regulatory molecules bind to it, leading to increased gene expression, which, in turn, increases the risk of developing breast cancer.

By comparing all of the tiny differences in the genomes of people with breast cancer to those in a control population, FGFR2 had been flagged up as a region of the genome that is consistently different between the two groups. FGFR2 encodes a protein that sits in the membrane of cells and works in a signalling pathway important for cell growth.

This study, conducted in the Cancer Research UK Cambridge Research Institute, has identified just what these slight genetic changes mean at the molecular level. FGFR2 genes altered at two specific points have a greater affinity for binding certain transcription factors-regulatory proteins that influence gene expression patterns. Because of this additional binding, more FGFR2 protein is produced in cells carrying the mutation and this seems to be enough to increase the risk of cancer a small but significant amount.

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Interestingly, the mutation occurs not in the coding regions of the genes (the bits translated into protein by cellular machinery), but rather, in an intron (a region of DNA found amongst the coding bits). The two alterations therefore affect the regulation of the gene, but the proteins produced are normal; there is too much of it for the cells to develop as normal, instead becoming cancerous.

Citation: Meyer KB, Maia A-T, O'Reilly M, Teschendorff AE, Chin S-F, et al. (2008) Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biol 6(5):e108. doi:10.1371/journal.pbio.0060108

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"To understand what's happening in any battle, you need to know what's going on with the soldiers as well as with the enemy, so investigating the nature of CTL responses in HIV infection requires monitoring both virus and host responses simultaneously," Streeck says. "Therefore, it is important that HIV vaccine trials evaluate the immune responses carefully in the context of the virus, as the virus might already have evolved. The inability of the vaccine-induced immune response to cross-recognize the infecting virus might actually have contributed to the failure of recent HIV vaccine trials." Streeck is a research fellow in Medicine at Harvard Medical School.

The senior author of the PLoS Medicine report is Marcus Altfeld, MD, PhD, of PARC-MGH. Additional co-authors are Zabrina Brumme, PhD, Kristin Cohen, Jonathan Jolin, Angela Meier, MD, Chanson Brumme, Eric Rosenberg, MD, Galit Alter, PhD, Todd Allen, PhD and Bruce Walker, MD, of MGH-PARC, and Michael Anastario, PhD, Uniformed Services University of the Health Sciences. The study was supported by funding from the National Institutes of Health, the German Academic Exchange Service, and the Canadian Institutes of Health Research.

Massachusetts General Hospital established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

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