Genetic Markers of Colorectal Cancer Risk Identified

Three separate genome-wide association studies published online July 8 in Nature Genetics have identified a locus on chromosome 8 (8q24) in which several single nucleotide polymorphisms (SNPs) - changes in a single nucleotide of DNA - confer significantly increased risk of colorectal cancer (CRC). This locus has been implicated in previously published research as playing a role in prostate cancer risk.

The first study, led by a Canadian research team, used a four-stage process to identify and validate SNPs associated with CRC risk. The first stage evaluated three different sets of SNPs, containing more than 50,000 single nucleotide changes, in 1,257 people with colorectal cancer and 1,336 controls from Ottawa. The second stage tested 1,143 potential markers of risk identified in stage 1 in two different case-control populations: one from Seattle, Washington, and one from Newfoundland. The third stage tested 76 markers replicated in the previous 3 populations in a case-control population from Scotland with early-onset CRC. The nine markers further validated in this population were then tested in a fourth stage in a second, independent case-control series from Scotland.

Two of the risk associations confirmed in stage 3 were replicated in stage 4, and the investigators compared these loci, 8q24 and 9p24, with results from several European studies, leading to validation of two SNPs in 8q24 that confer significantly increased risk of CRC. This multistep replication process is in keeping with recent guidelines published in Nature by the NCI-NHGRI Working Group on Replication in Association Studies.

The second study, from the University of Southern California, directly examined 6 variants previously identified as genetic markers of prostate cancer risk in 1,124 patients with invasive CRC and 4,573 controls, all taken from a multi-ethnic study population including people of African American, Japanese American, Native Hawaiian, Latino, and European descent.

One variant on 8q24 identified as significantly associated with CRC risk in this group was then tested in 683 additional CRC cases and 938 controls in 2 substudies of patients of Japanese American and European descent. The variant was replicated as a marker of CRC risk in one study but not the other; however, the marker remained significantly associated with CRC risk in a pooled analysis of all three studies.

The third study, from the United Kingdom, successfully genotyped more than 550,000 SNPs in 930 people with familial CRC and 960 controls, designated as panel A in the study. They also identified SNPs at 8q24 as being associated with CRC risk. The investigators then tested the SNP most strongly associated with CRC risk in 3 different case-control panels (panel B comprised 4,361 patients with CRC and 3,752 controls; panel C comprised 1,901 people with CRC and 1,079 controls; and panel D comprised 1,072 people with CRC and 415 controls). Only patients in panel D had a familial history of CRC.

Pooled data from the original set of patients and the three validation panels "provided unequivocal evidence for a relationship between [the SNP] and risk of CRC," stated the authors. Further analysis of the data provided evidence that the SNP may also be associated with an elevated risk of developing adenomas - noncancerous tumors - in the colon or rectum. This observation led the investigators to suggest that the locus on chromosome 8 may be involved in tumor initiation rather than progression.

Genetic Variations Linked to Increased Prostate Cancer and Decreased Diabetes Risks

A genetic study in Icelandic men with prostate cancer and several healthy control groups uncovered two genetic variations associated with moderate increase in the risk for prostate cancer and, in the case of one variation, a simultaneously protective effect against type 2 diabetes (T2D), according to results published online July 1 in Nature Genetics.

The study involved a genome-wide association scan to search for gene sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with the disease and 11,290 control subjects. Follow-up studies with three additional case-control groups confirmed an association of two variants on chromosome 17 with prostate cancer. One of the variants is in the TCF2 gene, which the scientists demonstrated also confers protection against T2D.

The two genetic variations pose only relatively small increased risks in individuals for prostate cancer. However, because the variations are so common, they have an estimated joint population-attributable risk (PAR) of 36 percent for the disease, "which is substantial from a public health viewpoint," the researchers noted.

The scientists were "most intrigued" by the counterbalancing of risks for prostate cancer and T2D with the TCF2 variation. "The discovery of a sequence variant in the TCF2 gene that accounts for at least part of the inverse relationship between these two diseases provides a step toward understanding the complex biochemical checks and balances that result from the pleiotropic [multiple effects] impact of singular genetic variants," they commented. Previous explanations of the well-established inverse relationship between prostate cancer and T2D have centered on the impact of the metabolic and hormonal environment of diabetic men.

Second HPV Vaccine Shows Early Positive Results

Positive interim results for a candidate vaccine to prevent infections by human papillomavirus (HPV) types 16 and 18 were published online in The Lancet June 28. The vaccine Cervarix was 90 percent effective in preventing grade 2 or 3 cervical intraepithelial neoplasias (CIN2+) that contained DNA from either virus type.

The results come from a large international trial of 18,644 women aged 15-25 sponsored by the drug's manufacturer, GlaxoSmithKline Biologicals. The trial design called for analysis of early results after 23 cases of CIN2+ were detected. Two of these cases were among the 9,258 women receiving the vaccine, and 21 were among the 9,267 controls who received a hepatitis A vaccine. The mean follow-up time was 14.8 months.

In an editorial, Drs. Jessica A. Kahn of the University of Cincinnati and Robert D. Burk of the Albert Einstein College of Medicine wrote, "These interim data are encouraging." But they noted that the paper does not provide information about the public health impact of vaccination "in real world settings" because the report does not provide estimates of the reduction in overall rates of CIN2+. They stress that vaccination of young adolescents is likely to have the greatest public health benefit, but that continued screening will still be required after vaccination.    

A separate phase III trial testing Cervarix, cosponsored by NCI with support from the NIH Office for Research on Women's Health and the Costa Rica Ministry of Health, is now underway in Costa Rica. This trial should provide additional information about the public health impact and efficacy of the vaccine.

International Programs Seek Applications

NCI's Office of International Affairs (OIA) is seeking applications to two projects.

The U.S.-Japan Cooperative Cancer Research Program (USJCCRP) began in 1974 and is coordinated by NCI and the Japan Society for the Promotion of Science. With the assistance of OIA, USJCCRP is establishing an annual workshop in basic, clinical, or epidemiological/behavioral science to support cancer research and clinical care.

The workshop venue will alternate between Japan and the U.S. For 2007-2008, USJCCRP will provide support for a basic science cancer workshop. Participation will be limited to 20 attendees from each country, allowing for a small number of participants from other countries. Requests for proposals (RFPs) will be conducted by an open call each June, with an application deadline in September, selection in October, and the workshop held between November and March.

The RFP for the 2007-2008 meeting was released on June 29. Individuals with the skills, knowledge, and resources to plan and conduct the proposed workshop are invited to develop an application for support. The first workshop can focus on any area of basic science. However, USJCCRP is particularly interested in receiving proposals in 1) regulation angiogenesis and lymphangiogenesis in cancer cells, 2) nanotechnology applications in cell imaging, diagnosis, and treatment, and 3) genomics and proteomics of cancer cells. More information and an application form can be found at http://www.cancer.gov/oia/US-JAPAN-CCRP.

The Ireland-Northern Ireland-NCI Cancer Consortium recently announced a call for applications in its Joint Research Projects in Cancer 2007.

This project aims to develop strong and sustainable relationships between cancer researchers and institutions in Ireland and the U.S. by supporting a shared postdoctoral researcher working on a research project of mutual interest. The project is awarded on a full-time basis over 3 years and is open to cancer researchers working on the island of Ireland or in the NCI intramural or extramural program.