Also in the March 10 JNCI

March 10, 2009

Folic Acid Supplement Use Associated with Increased Risk of Prostate Cancer

Men who took a daily folic acid supplement had more than twice the risk of prostate cancer compared with men who took a placebo, according to a secondary analysis from the Aspirin/Folate Polyp Prevention Study (AFPP).

The primary goal of the AFPP study was to determine the impact of aspirin and folate on colon polyps in men and women who were at high risk of disease. The effect of folate supplementation on prostate cancer risk was unknown.

To learn how folate supplements might affect prostate cancer risk, Jane Figueiredo, Ph.D., of the Keck School of Medicine at the University of Southern California in Los Angeles, and colleagues analyzed prostate cancer incidence among 643 men who were randomly assigned to folate or placebo in the AFPP study and who enrolled in an extended follow-up study.

The estimated prostate cancer risk was 9.7 percent at 10 years in men assigned to folate supplements, compared with 3.3 percent in men assigned to placebo; the difference was statistically significant. In contrast, baseline dietary folate intake and plasma folate showed a trend toward reduced risk of prostate cancer, although the difference did not reach statistical significance.

"In conclusion, this clinical trial provides evidence that daily supplementation with 1 mg of folic acid was associated with an increased risk of prostate cancer. It is unclear why dietary and plasma levels among non-multivitamin users may be inversely associated with risk. These findings highlight the potentially complex role of folate in prostate carcinogenesis," the authors write.

In an accompanying editorial, Alan Kristal, Dr.P.H., of the Fred Hutchison Cancer Research Center in Seattle, and Scott Lippman, M.D., of the M. D. Anderson Cancer Center in Houston, write that the negative data on folate supplementation and prostate cancer adds to a growing body of data indicating that micronutrient supplementation does not lower cancer risk. "It is safe to conclude that cancer prevention is not going to be as simple as recommending high-dose micronutrient supplements for middle-aged and older adults," the editorialists write.

The editorialists suggest that it is time for researchers to go back to large, epidemiological studies, using improved modern methods, to look for ways in which diet can lower cancer risk. Additionally, they say, investigators should first complete small studies in humans to understand how dietary change or supplements affect biological mechanisms related to cancer, and only then move to large scale randomized trials.


Herpesvirus 8 K1 Oncoprotein Directly Inhibits Fas-Mediated Cell Death

Human herpesvirus 8 (HHV-8) K1 oncoprotein binds directly to the Fas protein in tissue culture cells and blocks Fas-mediated cell death.

HHV-8 is associated with Kaposi sarcoma in humans and expression of the HHV-8 K1 oncoprotein leads to lymphoma in transgenic mice. Previous work suggested that K1 inhibits Fas-mediated cell death but the exact mechanism was unknown.

In the current study, Felipe Samaniego, M.D., of the University of Texas M. D. Anderson Cancer Center in Houston, and colleagues transfected human cell lines with either a wild-type K1 gene or a K1 gene lacking an Ig domain, which is often involved in protein-protein interactions.

Fas activity was inhibited in cells that expressed wild-type K1 but not in cells expressing the Ig-deleted K1 mutant. Wild-type K1 protein expression protected mice from death due to stimulation of the Fas receptor, but the Ig-deleted mutant protein did not.

"The current results show that the HHV-8 protein K1 physically associates with Fas and thereby dis¬rupts initiation of Fas-mediated apoptotic signaling induced by agonistic antibodies and [Fas ligand]," the authors conclude.

Contact: Scott Merville,; (713) 792-0661

Silencing HPV Genes Induces Cell Death in Oropharyngeal Cancer Cell Lines

Repression of human papillomavirus type 16 (HPV16) oncogenes E6 and E7 led to restoration of tumor suppressor gene activity and induced programmed cell death in oropharyngeal cancer cells grown in culture.

HPV16 is known to cause cervical cancer and has been associated with oropharyngeal cancers. However, mechanistic data showing a causal relationship between HPV16 and head and neck cancers has been lacking.

In the current study, Amanda Psyrri, Ph.D., of Yale University School of Medicine in New Haven, Conn., and colleagues introduced short hairpin RNAs (shRNAs) into HPV16-positive oropharyngeal cell lines. The shRNAs were designed either to interfere with HPV oncogenes E6 and E7 or to encode a scrambled control sequence.

Inhibition of the viral oncogenes resulted in renewed expression of endogenous tumor suppressor proteins p53 and pRB. Apoptosis increased in two oropharyngeal cancer cell lines from less than 13 percent in cells expressing the control shRNA to more than 70 percent in cells expressing the E6/E7-inhibiting shRNAs.

"These results, along with epidemiological and molecular pathology studies, con¬tribute to the establishment of a causal association between HPV and oropharyngeal cancer," the authors write.

Contact: Renee Gaudette,; (203) 436-8533

ABO Blood Groups May Affect Pancreatic Cancer Risk

Individuals with blood type O appear to have a lower risk of pancreatic cancer than individuals with blood types A, B, or AB, according to an analysis of two large independent cohort studies.

Genetic risk factors for sporadic pancreatic cancer are largely unknown. Previous studies have suggested that ABO blood types may be associated with several different malignancies, including pancreatic cancer.

In the current study, Brian Wolpin, M.D., of the Dana-Farber Cancer Institute in Boston, and colleagues examined the association between blood type and pancreatic cancer incidence in 107,503 individuals who participated in either the Nurses' Health Study or the Health Professional Follow-Up Study.

The age-adjusted incidence rate for participants with blood type O was 27 per 100,000 person-years, compared with 36 for individuals with blood type A, 41 for individuals with blood type AB, and 46 for individuals with blood type B.

"In two large, independent prospective cohorts, we observed a sta¬tistically significantly elevated risk for incident pancreatic cancer among participants with blood group antigens A or B compared with those with blood group O," the authors write. "Additional investigation is necessary to further confirm these findings and to determine the potential mechanisms by which ABO antigens may influence pancreatic cancer risk."

Contact: Bill Schaller,; (617) 632-5357

Also in the December 9 JNCI:
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