Clinical OMICS

MAY-JUN 2017

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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36 Clinical OMICs May/June 2017 www.clinicalomics.com In the Lab Some Lab-Grown Stem Cells Develop Cancer-Linked Mutation Recent work by Harvard researchers, detailed in the journal Nature, determined that human pluripotent stem cells are prone to develop mutations in the TP53 gene, which ordinarily helps suppress cancer. The mutated versions of the TP53 found by the Harvard team, however, tend to drive cancer development suggest- ing the need to screen lab-grown stem cells for deleterious mutations. "[We] identified five unrelated hES cell lines that carried six mutations in the TP53 gene that encodes the tumour suppressor P53," wrote the article's authors. "The TP53 mutations we observed are dominant negative and are the mutations most commonly seen in human cancers. We found that the TP53 mutant allelic fraction increased with passage number under standard culture conditions, sug- gesting that the P53 mutations confer selective advantage." The Harvard team sequenced the protein-coding genes of 140 human embry- onic stem cell (hES) cell lines—26 of which were developed for therapeutic pur- poses using Good Manufacturing Practices, a quality control standard set by regulatory agencies in multiple countries. The remaining 114 human pluripotent stem cell lines were listed on the NIH registry of human pluripotent stem cells. This gene-sequencing exercise was followed by computational work that allowed the scientists to identify mutations present in a subset of cells in each cell line. The scientists also mined published RNA sequencing data from 117 human plu- ripotent stem cell lines, and observed another nine TP53 mutations, all resulting in coding changes in the DNA-binding domain of P53. "In three lines," the authors of the Nature paper detailed, "the allelic fraction exceeded 50%, suggesting additional selective advantage resulting from the loss of heterozygosity at the TP53 locus." These findings suggest that cell lines should be screened for mutations at vari- ous stages of development as well as immediately before transplantation. "Our results underscore the need for the field of regenerative medicine to pro- ceed with care," said the study's co-corresponding author Kevin Eggan, Ph.D. "[They] indicate that an additional series of quality control checks should be implemented during the production of stem cells and their downstream use in developing therapies. Fortunately, these genetic checks can be readily performed with precise, sensitive, and increasingly inexpensive sequencing methods." arrays, the authors showed a significant number of differentially expressed genes in the peripheral blood between the three clinical phenotypes with high pre- dictive accuracy (sensitivity, specificity, PPV, NPV ), even when adjusted for prev- alent incidene of each phenotype. Research Links Genetics to Early-Onset Pancreatitis in Pediatric Patients A study published in The Journal of Pedi- atrics led by Matthew Giefer, M.D., director of gastrointestinal endoscopy at Seattle Children's Hospital suggests that early-on- set pancreatitis in children is strongly associated with certain genetic mutations and family history of pancreatitis. For the research, Dr. Giefer and col- leagues analyzed 342 children ages from birth to 18 with acute recurrent pan- creatitis (ARP) and chronic pancreatitis (CP) from INSPPIRE (International Study Group of Pediatric Pancreatitis: In search for a cure), the nation's first and only mul- ticenter, National Institutes of Health- funded pediatric pancreatitis registry. The team found strong correlations between certain pancreatitis-associated genes and early-onset (before the age of 6) development, the study noted, with 71% possessing at least one pancreatitis-as- sociated gene mutation— sig nificantly Steve Debenport/ Getty Images luismmolina/ Getty Images (continued from previous page) (continued on page 38)

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