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Sequencing of Circulating Tumor DNA Detects Early Cancers

NEW YORK (GenomeWeb) – A Johns Hopkins University-led team has shown that it is possible to find early cancer cases using a sequencing-based liquid biopsy approach designed to dial down sequencing errors and false-positives with in-solution capture and deep sequencing.

For their proof-of-principle analysis, published online today in Science Translational Medicine, the researchers did liquid biopsies on 200 individuals with colorectal, breast, lung, or ovarian cancer, and nearly four dozen healthy controls, using an ultra-deep sequencing approach known as targeted error correction sequencing (TEC-Seq) to assess a panel of 58 cancer-related genes in circulating, cell-free DNA.

"The challenge was to develop a blood test that could predict the probable presence of cancer without knowing the genetic mutations present in a person’s tumor," senior author Victor Velculescu, co-director of cancer biology at Johns Hopkins University, said in a statement.

Indeed, the team picked up cancer-associated somatic mutations in around 59 percent to 71 percent of the 138 early stage cancer patients, depending on the cancer type considered. In some 16 percent of the healthy individuals, the group saw subtle changes implicated in an age-related process that dials down blood cell progenitor clones, though no solid cancer-related alterations turned up in the control group.

The work was co-authored by investigators from the liquid biopsy firm and Johns Hopkins spinout Personal Genome Diagnostics, which uses TEC-Seq as part of its PlasmaSelect protocol.

"This study shows that identifying cancer early using DNA changes in the blood is feasible, and that our high accuracy sequencing method is a promising approach to achieve this goal," said Velculescu, who is also a PGDx cofounder.

The study's first author, Johns Hopkins' Jillian Phallen, presented findings for 179 cancer patients and 44 healthy controls during a presentation at this year's American Association for Cancer Research annual meeting in April.

After testing the TEC-Seq method in dilutions of DNA soup derived from tumor cell lines, the researchers took a crack at using the liquid biopsy approach to assess blood plasma samples from 44 seemingly healthy control individuals and 194 individuals with breast, colorectal, lung, or ovarian cancer, including 138 individuals with early stage (stage I or II) cancer.

In the process, the team captured 80,930 bases of DNA sequence from each individual's blood and generated 30,000-fold average coverage across the sequences, coding for 58 cancer-related genes. Once germline mutations, sequence artifacts, and genetic changes that could be attributed to pre-leukemic conditions were filtered out, the group saw telltale cancer-related mutations in 62 percent of individuals with early stage cancer.

Detection rates were highest for individuals with colorectal cancer, the researchers noted, while breast cancer patients tended to have lower levels of circulating tumor DNA. More than 70 percent of the early stage colorectal cancer cases had ctDNA identified by TEC-Seq, for example, compared with 59 percent of the stage I or II breast or lung cancers.

Around 72 percent of the blood borne mutations that tipped investigators off to the presence of cancer also turned up in the same individual's tumor — at least across the 100 cases where tumor tissues were available. Likewise, most of the alterations identified in blood samples from six late-stage lung cancer patients were detected again in ctDNA isolated during subsequent blood draws.

Finally, the investigators showed that they could track treatment response and/or disease progression in 31 individuals with colorectal cancer after tumor resection surgery. There, they noted, enhanced levels of ctDNA after surgery tended to coincide with poorer survival overall and reduced time to disease progression.

Based on such results, the authors argued that "the amount and type of ctDNA at the time of diagnosis may provide additional insight related to patient prognosis that could inform further clinical intervention."

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