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Columbia U, Canadian Team Discovers Contagious Clonal Clam Cancer

NEW YORK (GenomeWeb) – A study appearing online today in Cell suggests that a leukemia-like disease that's been ravaging soft-shell clam populations off of North America's east coast for decades is caused by a transmissible clonal cancer cell line that originated in a single clam and has since spread horizontally between individuals. 

Following from a prior study that picked up the same highly expressed retrotransposon — called Steamer — in several soft-shell clam leukemia samples, researchers from Columbia University and Environment Canada used PCR-based testing to track insertion sites in cancerous tissues from clams collected off the coast.

The team's data pointed to overlapping Steamer insertion sites in the cancers that were missing from unaffected host tissues. And more detailed microsatellite- and SNP-based analyses revealed that the leukemic cells shared genotypes that clustered with one another, but did not match those found in host tissue. Together, such results point to the ongoing spread of related, infectious cancer cell lines that originated from the a single clone and have since diverged slightly from one another.

The patterns detected "could only really be explained if the tumor were, in fact, a clone — a single cell clone that is spreading," senior author Stephen Goff, a biochemistry and molecular biophysics researcher at Columbia, told GenomeWeb.

Transmissible cancer cell lines have been described only rarely in the past. The most notable examples include a sexually transmitted venereal tumor disease in dogs and the Tasmanian devil facial tumor disease, which is passed from one animal to the next by biting.

For their new analysis, Goff and colleagues focused on a leukemia-like disease called disseminated, or hemic, neoplasia that's been negatively impacting populations of the soft-shell clam Mya arenaria on the East Coast since the 1970s.

Although transmission of the disease between soft-shell clams was long documented, researchers had not been able to find a viral culprit or other infectious agent behind the often-deadly disease.

Goff and his team, who normally study mouse leukemia viruses, started doing research on the clam neoplasia after being contacted by a marine biologist who suspected a cancer-causing virus might be at play.

In a study published in the Proceedings of the National Academy of Sciences last year, the researchers used RNA sequencing on soft-shell clam hemolymph to show that the neoplasms are marked by dramatically elevated expression and copy numbers of the Steamer retrotransposon.

Whereas just two to 10 copies of Steamer are normally detected in the soft-shell clam genome, they found that the retroelement was dialed up to as many as 300 copies in the neoplasia.

To explore this in more detail for the current study, the researchers used inverse PCR to profile Steamer insertion sites in leukemic soft-shell clams from sites off of New York, Maine, and Prince Edward Island.

The team detected a dozen insertion sites. Of those, seven were shared across all of the leukemic samples. Another four were found in neoplastic samples from the New York and Maine sites alone, while a single Steamer insertion was specific to neoplasms in clams from Canada.

Through additional PCR-based genotyping on mitochondrial SNP and microsatellite DNA patterns in 11 healthy soft-shell clams and nine clams with neoplasms, the researchers verified the clonal nature of the clam leukemia cell lines, demonstrating that they differed genetically from non-cancerous tissues in affected host clams.

"Those genotypes were distinct from the host animal in which the disease was occurring," Goff said. "So this clone had not arisen from the host in the normal way."

Their results suggest that neoplastic cell lines cluster with one another genetically, although the transmissible cancer clones that are circulating in Canada and the US appear to fall in slightly different subgroups due to divergence in the time since the first clonal cancer arose.

It remains to be seen when that divergence occurred, since scientists have not yet gotten a handle on when the clonal clam cancer originated.

To that end, Goff and his team plan to sequence and compare targeted genes in multiple soft-shell clam neoplasms to try to reconstruct the age of the clonal line. The Steamer insertion sites studied so far are not particularly helpful for performing such dating, Goff explained, because retroelements tend to hop at unpredictable rates.

The team is also interested in looking more closely at Steamer and its potential role in inducing the oncogenic mutations that may have caused the cancerous cell line to spring up in the first place.

In addition, the researchers hope to tease apart the mode by which the cell lines colonize new animals, while screening animals such as clams, cockles, or oysters to see whether such contagious cancer cell lines are found in other marine bivalves.

"We normally don't worry about this in vertebrates because we have an immune system that prevents this, that rejects a tumor like this as foreign," Goff noted. "But invertebrates don't have an adaptive immune system and that may be why they're more susceptible to this."