Author Interviews, Cancer Research, Genetic Research / 10.10.2015

Huma Q. Rana, MD Clinical Director, Cancer Genetics and Prevention Dana-Farber Cancer Institute in BostonMedicalResearch.com Interview with: Huma Q. Rana, MD Clinical Director, Cancer Genetics and Prevention Dana-Farber Cancer Institute in Boston Medical Research: What is the background for this study? What are the main findings? Dr. Rana: -        Li-Fraumeni syndrome (LFS) is thought to be a rare, inherited condition that  causes high lifetime risks for multiple cancers.  It is caused by mutations in the TP53 gene.  Traditionally, only people with striking personal or family histories of cancer underwent genetic testing for TP53 mutations, as there are well-established testing criteria.   This gene was usually tested for in isolation, meaning not combined with testing of other genes.  Due to technological advances, namely multi-gene panels (MGP), many more people are having their TP53gene analyzed.    This included a patient of mine who somewhat surprisingly  tested positive for a TP53 mutation.    This led us to investigate whether people who test positive for TP53 mutations on MGPs are different from ones who test positive on traditional or single-gene (SG) testing. We compared individuals tested for TP53 single gene versus multigene panel testing to determine if there were differences in the percent of mutation carriers meeting current testing criteria for LFS.   Our data showed that 73% of individuals sent in for single gene testing of TP53 met Classic or Chompret (2009) criteria for LFS, whereas only 30% of those sent in for multi-gene panel testing met criteria (p=0.0000001).  When we looked at the most up-to-date testing criteria, which includes Classic, Chompret, or a personal diagnosis of early-onset breast cancer (age at ≤35), 85% of individuals in the single gene group who were positive met criteria, while only 53% of the mutation carriers identified on a multi-gene panel did.   These data suggest that multi-gene panel testing enables us to identify TP53 mutation carriers who may not have otherwise been identified if testing were limited to those who meet established LFS criteria. (more…)
Author Interviews, Fertility, Genetic Research / 09.10.2015

Rajiv McCoy, PhD Dept. of Genome Sciences Univ. of WashingtonMedicalResearch.com Interview with: Rajiv McCoy, PhD Dept. of Genome Sciences Univ. of Washington Medical Research: What is the background for this study? What are the main findings? Dr. McCoy:  Aneuploidy—the inheritance of extra or missing chromosomes compared to the typical 46-chromosome set—is extremely common in human embryos. The vast majority of aneuploidies result in preclinical pregnancy loss, often before the pregnancy is even recognized by the mother. This is thought to be the primary reason why only ~30% of all conceptions result in successful live birth. Many aneuploidies arise during egg formation, with the frequency increasing with maternal age. In addition to meiotic errors, a large proportion of aneuploidies affecting cleavage-stage embryos are mitotic in origin, arising during the initial post-fertilization cell divisions. These initial divisions are controlled by machinery contributed by the mother in the egg (before the embryo's genome has been activated). While these mitotic errors are frequent in cleavage-stage embryos, we found that they are rare in embryos at day-5 of development (the blastocyst stage), suggesting that embryos and/or cells with extensive mitotic errors do not survive to day 5. We discovered that some women have a greater propensity to produce embryos with mitotic errors than others, and our idea was that maybe differences in the mitotic machinery could help explain this. Using data from in vitro fertilized embryos screened by our collaborators at Natera, we found that women who have a particular version of a gene called PLK4 tend to produce more aneuploid embryos, regardless of age. This genetic variant is actually very common—more than half of people carry at least one copy—and is present in nearly all populations. PLK4 has a well-known role in ensuring the proper distribution of chromosomes. We also found that patients referred for embryo screening due to previous IVF failure had higher rates of mitotic error, which underscores the clinical importance of this form of whole-chromosome abnormality. (more…)