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Hopkins Researchers Seek Early Cancer Diagnosis using Tampon-borne Cell-free DNA

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NEW YORK (GenomeWeb) — Following promising early results, researchers from Johns Hopkins are expanding a project that used sequencing to detect cancer mutations in cell-free DNA from Pap smear fluids into a larger effort to also examine the vaginal fluids collected in tampons.

In November, the researchers, led by associate professor Luis Diaz, published their first data from a small pilot study of the tampon sequencing method in Obstetrics and Gynecology. In this study, the team analyzed DNA extracted from tampons used by women about to undergo surgery for a pelvic mass to see if they could detect TP53 mutations associated with the women's tumors in cell-free tumor DNA shed into the vaginal fluid.

Diaz also discussed the results at last month's annual meeting of the Association for Molecular Pathology.

Overall, the team hopes that its strategy — whether using tampons, Pap smear fluid, or other vaginal or pelvic samples — may allow the early detection of tumors like ovarian cancer, which are currently most often diagnosed when the disease is advanced and prognosis is very poor.

If Diaz and colleagues can make their sampling and sequencing method sensitive enough, they believe they may be able to detect mutated DNA shed from new, otherwise undetectable cancers.

In its recent tampon proof-of-concept study, the Diaz group enrolled 33 patients, eight of which ended up having advanced serous ovarian cancer and being included in the group's analysis. When Diaz and colleagues sequenced DNA isolated from these women's tampons — using a method they previously developed called  the Safe-Sequencing System (Safe-SeqS), which uses a barcoding strategy to distinguish errors from real variants — they found TP53 mutations in three of them, yielding an overall sensitivity of about 40 percent.

However, the group also discovered that three of the women had had tubal ligations, suggesting that it would be difficult or impossible for ovarian tumor DNA to travel to the vaginal fluid. Excluding these women, they recalculated the sensitivity as 60 percent.

For all three cases in which the group's tampon DNA analysis identified a TP53 mutation, it was identical to what was also found in the patients' tumor tissue, the researchers reported.

Since the tampon study and the group's previous pilot using Pap smears, the researchers have been working to expand their effort to include about 1,000 patients. Data from this project should be published some time in early or mid 2015, Diaz told GenomeWeb.

In ongoing research, the team is also testing the Safe-SeqS method in high-risk women rather than those who already have a known tumor.

These efforts include both women who are at high risk for developing an ovarian or endometrial tumor based on a cancer syndrome like Lynch syndrome or BRCA mutations, or because of treatment with a drug like tamoxifen, which raises the risk of endometrial cancer.

The hope is that the effort will establish whether it is really possible to detect tumor DNA in vaginal or cervical fluids as a first hint of cancer.

Because the researchers have not been able to detect as many cases of ovarian cancer as endometrial cancer in their early work, Diaz said that it will be important to develop either technological or biological strategies to increase the sensitivity of Safe-SeqS in order to advance the method for ovarian tumors.

Based on his group's earlier research, Diaz said at the AMP meeting that it is clear that different types of cancer shed different amounts of DNA into blood and other body fluids.

In separate work Diaz and colleagues are conducting in the colorectal cancer area, they have attempted to increase their ability to detect tumor DNA by having patients undergo stress tests, with the hope that this biological insult might cause the tumor to release more DNA, a kind of shaking of the tumor tree.

However, this strategy has not yet proven successful. "You can probably guess what happened. We had shedding of normal DNA and it wiped out tumor DNA so we couldn’t see it," he said.

For ovarian cancer, Diaz told GenomeWeb, the group is not looking at biological stimulation strategies as much as increasing the sensitivity of sampling methods and the technology of Safe-SeqS.

While their earlier research using Pap smear fluid had limited success in detecting ovarian cancer mutations, the researchers did see extremely high sensitivity for mutations associated with endometrial cancers, identifying 100 percent of these tumors in a group of 24 women.

If the group can replicate that sensitivity in a larger cohort, Diaz said that cervical fluid specimens or tampons might be developable as an actual sample type for clinical testing.

"Based on what we've seen, in the future, standard Pap smears should be more than good enough for endometrial cancer," he said.

Tampons may also be attractive because it might make cancer screening more accessible. "Imagine if you could just send your tampon to your doctor and get a diagnosis," Diaz said.

He added, however, that the group is still actively evaluating what the optimal sample collection vehicle might be. 

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