Clinical OMICS

MAY-JUN 2018

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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Page 37 of 51

In the Lab 36 Clinical OMICs May/June 2018 as it alters a well-known transcription factor binding site. From the litera- ture, we found that the DAAM1 gene is thought to be linked to cell migra- tion. That's very intriguing because mutation of DAAM1 only occurs in metastatic melanoma patients, and cell migration is related to metasta- sis. Thus, we were very interested in testing this gene, both for its ability to drive gene expression and because of the mutation's link to cell migration." The somatic eQTL for DAAM1 was situated 191 base pairs upstream of the gene. The DAAM1 protein is believed to have a role in a signaling pathway linked to the increased motility and invasiveness of cancer cells. Mutations at the somatic eQTL were associated with increased expression of DAAM1. By comparing the effects of wild-type versus mutated regulatory elements on expression of the reporter gene green fluorescent protein (GFP), the research- ers were able to confirm a causative relationship between the eQTL and the upregulation of gene expression. Experiments that probed the rela- tionship between higher DAAM1 expression and cell motility showed an association between DAAM1 upregulation and a more invasive cell phenotype. Furthermore, cells that over-expressed the DAAM1 gene "migrated with significantly greater persistence" and "invaded for lon- ger distances" than did cell in which DAAM1 was not over-expressed. Subsequent studies focused on two additional somatic eQTLs. One was located in the promoter of the MTG2 gene and was associated with down-regulation of MTG2 expres- sion. It was present in multiple types of cancer including lung adeno- carcinoma and sarcoma. The other somatic eQTL was found situated in the enhancer region of the HYI gene. It led to increased HYI expression and was found in 21% of melanoma tumors studied. All three genes—DAAM1, MTG- 2, and HYI—were chosen for further experimentation because of their expression levels and available knowl- edge about their regulatory regions. Another factor contributing to the selection of these genes was the impor- tance of doing the follow-on studies in tumor cell lines that could as closely as possible represent those of the patients in the cancer database and the ease of access to those cell lines. Conclusions Much of the interest these days in look- ing at patients with cancer and trying to characterize disease-related gene mutations is focused on somatic muta- tions in either oncogenes or tumor suppressor genes. "This study starts to show that there are probably can- cer-relevant mutations in other parts of the genome that we need to start paying attention to," said Kreisberg. "The loci being mutated that we point out in the paper, which are ones that map to transcription factor binding sites, are experimentally the lowest hanging fruit. If we see a transcription factor binding site being created or destroyed, that seems like a good place to start doing experiments. But we've only looked at 3 of 193 somatic eQTLs. There's a lot more room to characterize more of these and more broadly under- stand their functional consequences. Understanding these better might reveal new vulnerabilities." (continued from previous page) Congenital Heart Defects in Offspring Elevate Maternal Cardiac Disease Risk Investigators at McGill University and the University of Montreal Hospital Research Center have found that women who give birth to infants with congenital heart de- fects may have an increased risk of car- diovascular hospitalizations later in life. The new study published in the journal Circulation, which looked at the health data of more than one million women, is the first to show congenital heart defects in newborns may be a marker for an in- creased risk of their mothers developing heart problems, including heart attack and heart failure, years after pregnancy. "Caring for infants with critical heart de- fects is associated with psychosocial and financial stress, which may increase the mothers' long-term risk for cardiovascular disease," explained lead study investigator Nathalie Auger, M.D., an epidemiologist at the University of Montreal Hospital Re- search Centre. How heart defects in infants relate to post-pregnancy cardiovascular disease in their mothers is currently unclear, the study notes, and a genetic component cannot be excluded. Also, because 85% of infants with heart defects now survive past adoles- cence, the psychosocial impact of congen- ital heart disease on caregivers may have a cumulative effect over the long term. n MHJ / Getty Images

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