Genomics takes center stage in cancer prevention, treatment

DENVER-Candidate genes and epigenetics are key components in the effort to develop and deploy personalized cancer prevention and treatment. Several studies at the AACR took a closer look at both those research pathways.

"There are those of us who believe that prevention is better than trying to identify drugs for treatment after a person has cancer," said Peter Shields, MD, deputy director of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC. "Today we are talking about personalized medicine in the context of personalized prevention. We are getting closer to understanding the individual risks for cancer that may be developing."

Meanwhile, "epigenetics is massive," said Owen O'Connor, MD, PhD. "Epigenetics is this idea that we can turn genes on and turn genes off using classes of drugs using Histone deacetylase inhibitors and hypomethylation."

Candidate genes

Researchers at Fred Hutchinson Cancer Research Center in Seattle investigated if eating charred red meat and cigarette smoking had different effects on people who had polymorphisms of the mEH gene, which is linked to metabolism of carcinogens (abstract 2116). Both are believed to be related to development of colon cancer.

Andrea N. Burnett-Hartman, MPH, and colleagues queried 529 patients with adenoma, 691 patients with hyperplastic polyps, 227 patients with adenomas and hyperplastic polyps, and 772 healthy control patients regarding lifestyle.

She said that eating charred meat appears to increase risk of colon cancer, but that increase does not reach statistical significance whether the individual eats meat more than three times a week or has favorable or unfavorable genetics.

Smoking cigarettes, on the other hand -- especially if the individual has personal smoking history that exceeds 22 pack-years of consumption -- results in a 65% increase risk of developing adenomas and a 2.38-fold risk of developing hyperplastic lesions.

"Even having favorable genetics is not going to protect you from the carcinogenic effects of smoking," said Ms. Burnett-Hartman, who is a doctoral candidate at the University of Washington.

Another group at Hutchinson Center looked at relationships between colon cancer and certain COX1 and COX2 polymorphisms.

Anna Coghill, MPH, and colleagues identified 17 COX1 and 13 COX2 tag single nucleotide polymorphisms. Ms. Coghill said that COX2 rs4648261 was linked with a reduction in colorectal cancer risk of between 40% and 68%. No other single nucleotide polymorphism studied among the 1584 cases and 2516 siblings in the Colon Cancer Family Registry appear to have any influence in the risk of developing colon cancer, she said (abstract 2115).

"If we can identify which patients are going to benefit from these drugs, we can more effectively target prevention," said Ms. Coghill, who is a graduate research assistant. The group was led by Cornelia Ulrich, PhD.

For example, there appears to be a benefit in treatment with COX2 inhibitors such as rofecoxib (Vioxx) or nonsteroidal anti-inflammatory drugs such as ibuprofen or aspirin. But some of these drugs appear to raise heart disease risk, she said.

Epigenetics

Nutritional research recommends that women looking to conceive and pregnant women take folic acid in an effort to prevent neural tube defects. But there are concerns about the side effects of too much folate and whether folate intake truly influences epigenetics later in life.

"Folate is essential for DNA methylation," explained Karen K. Sie, MSc, a research scientist at the University of Toronto. "Early folate nutrition plays an important role in epigenetic programming of the offspring and is related to the development of chronic disease later in life, including cancer."

Ms. Sie's group looked at the effect of in utero and postnatal folic acid supplementation on genomic DNA methylation in the offspring. In this animal study, female rates were placed on either a controlled diet (2 mg folic acid/kg) or supplemented diet (5 mg folic acid/kg) for three weeks prior to breeding. They remained on the diet throughout pregnancy and lactation. Folate levels were then measured in their offspring (abstract 75).

Genomic DNA methylation was measured in the colon and liver as were plasma folate, plasma homocysteine (Hcy), and liver folate concentrations. The authors found that plasma and liver folate concentrations accurately reflected dietary folic acid levels (p<0.001) and were higher in the supplemented FA groups. Plasma Hcy was significantly lower in animals fed the supplemented diet (p<0.001).

The offspring in the supplemented diet group had a significantly lower genomic DNA methylation than pups on the control diet (p<0.05). The data suggested that folate supplementation provided in utero and postnatally significantly influenced genomic DNA methylation in the offspring.

"What's important is that you not take home the message from this presentation that folic acid may be bad for women who are pregnant," Dr. Shields stressed. "There's a lot of research that has to be done to even think that there is a risk. This study doesn't use cancer as an endpoint by methylation. Nonetheless, we need to have a better understanding of the biology behind the recommendations."

In other notable studies:

• Researchers from San Antonio suggested that the mTOR inhibitor temsirolimus has exhibited promising anticancer activity for the treatment of durg-resistant renal cancer. They found that vorinostat (Zolinza) significantly enhanced the anticancer activity of temsirolimus in vitro and in xenograft models of renal cancer. Vorinostat sensitized all nine renal cancer cell lines to temsirolimus-induced death. The temsirolimus and vorinostat combination reduced tumor burden to a greater extent in two renal cancer xenograft models when compared with either single agent treatment (abstract LB-30).
   
• Promoter CGI hypermethylation in combination with other epigenetic alterations is associated with gene silencing, according to a group from the University of Missouri in Columbia. In their study, they demonstrated that the promoter CpG islands (CGIs) of SOX2 and KLF4 are methylated in two aggressive B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma (BL). The CGI methylation was tested for 10 genes: SOX2, KLF4, HOXD10, COX2, DLC-1, PCDHGA12A, HIN1, SLC26A, CDH1, and CD44. The researchers noted dense methylation of the SOX2 gene was observed in all three cell lines and one DLBCL patient. Only weak methylation bands were seen in all other patients (LB-166).
   
• Japanese investigators found that inflammation-related genes, with parallel expression levels to methylation levels, could be important for methylation induction in gastric cancer. In their study, they illustrated that Helicobacter pylori infection causally induced aberrant DNA methylation. They found that methylation levels increased depending upon the infection duration and reached high levels (up to 4.5%) at 50 weeks after infection. H pylori eradication led to a decrease of methylation levels to as low as 9% of those before eradication. An assessment of the association between methylation induction and inflammatory gene expression demonstrated that methylation levels paralleled those of inflammatory cell markers Cd3g, Cd14, and Ela2 and inflammation-related genes Cxcl2, Il1b, Nos2, and Tnf (abstract 3380).

Additional reporting by Shalmali Pal.