Current estimates hold that 21% of all human cancers are linked to infections. But some experts believe this figure is too low and is headed substantially higher.

Fueled by the success of vaccines for the hepatitis B virus and high-risk human papillomaviruses, which offer the first-ever means of preventing specific widespread cancers by vaccination, investigators are hunting for additional infectious causes of common malignancies. The search is focused on viruses, since they are already implicated in 64% of the known infection-related cancer burden, with bacteria and parasites accounting for the remainder.

One of the world’s most celebrated oncovirus hunters is Dr. Harald zur Hausen, winner of the 2008 Nobel Prize in Medicine for his work on human papillomaviruses as the major cause of cervical cancer. He sees a number of other malignancies as being prime candidates for potential linkage to infections, including childhood lymphoblastic leukemias, basal cell carcinomas, Epstein-Barr virus–negative Hodgkin’s lymphomas, colorectal and breast cancers, and lung cancers in nonsmokers.

The TTV (torque teno virus) family shows particular promise in this regard. The TTVs, first described by Japanese investigators in 1997 (Rev. Med. Virol. 2007;17:45-57), are an extremely heterogeneous family of single-strand DNA viruses. There are well over 100 genotypes. The torque teno viruses are widespread in all human populations. They have been found in umbilical cord blood and are vertically transmitted from mother to child, even prenatally. They frequently rearrange their genomes; and transmissibility and replication have been demonstrated to occur even for small portions of the TTV genome, according to Dr. zur Hausen, professor emeritus at the German Cancer Research Center, Heidelberg.

The TTVs are known to replicate in lymphatic and bone marrow cells – the precursor cells of leukemia. In every cell line of acute lymphoblastic leukemia and Epstein-Barr virus–negative Hodgkin’s lymphoma analyzed by Dr. zur Hausen and his coworkers, they have found the same highly conserved region of TTV DNA.

Of note, TTV load is known to be reduced by interferon. This finding is consistent with the epidemiologic observation that infants who experience multiple upper respiratory infections and other infections during their first year of life seem to be protected against childhood leukemias. The hypothesis is that bursts of increased interferon production in response to multiple infections prevents levels of an interferon-sensitive putative leukemogenic agent – perhaps a TTV – from reaching critical mass.

Dr. zur Hausen is particularly attracted to the possibility that cattle may play a role in some human cancers. He hypothesizes that some as-yet unidentified bovine virus, which is nononcogenic in its normal host, can become carcinogenic when transmitted to humans. Multiple lines of circumstantial evidence support this notion. For example, basal cell carcinomas are known to have a predisposition to arise in smallpox vaccination scars. Smallpox vaccines were prepared by inoculating vaccinia virus into the skin of calves and then harvesting the crusted skin, which could in theory contain contaminating bovine viruses.