Genetics Journal Club: 2017-18

This virtual journal club is intended to provide a way for health care practitioners to see new literature in genetics and to learn about developments in the field.

Articles on topics in medical genetics will be posted monthly, or more often if a particularly timely article is published.  To participate, read the article and then add your comments to participate in the online discussion. 

Can genetic information catch a killer?  And, cost you your privacy?

In the recent NEJM essay p53 and me, Shekinah N.C. Elmore describes the experience of living with a genetic diagnosis as "flying between fatalism and denial".  Dr. Elmore was diagnosed with Li–Fraumeni syndrome during her 1st year of medical school having already survived childhood rhabdomyosarcoma and simultaneous diagnoses of breast and lung cancer as an adult.  Dr. Elmore explores what it means in her life to have this genetic knowledge and how it affects her life - and what types of information would help her and others doing genetic testing in the future.  

This article reports the results of two phase 1-2 studies studied on the use of a gene therapy. In these studies, patients with transfusion-dependent β-thalassemia received gene therapy to assess if this therapy would substitute for the standard therapy, red-cell blood transfusions. The researchers were assessing both the safety and the efficacy of this gene therapy. You can read the results of this study in the New England Journal of Medicine.

Thompson, A. A., Walters, M. C., Kwiatkowski, J., Rasko, J. E., Ribeil, J. A., Hongeng, S., ... & Moshous, D. (2018). Gene therapy in patients with transfusion-dependent β-thalassemia. New England Journal of Medicine, 378(16), 1479-1493.

To learn more about this area of gene therapy, explore additional readings from Himmelfarb Library's full-text collection:

• Boulad F, Mansilla-Soto J, Cabriolu A, Rivière I, Sadelain M. Gene Therapy and Genome Editing. Hematol Oncol Clin North Am. 2018 Apr;32(2):329-342. doi: 10.1016/j.hoc.2017.11.007. Epub 2018 Jan 9. Review. PubMed PMID: 29458735.
• Ferrari G, Cavazzana M, Mavilio F. Gene Therapy Approaches to Hemoglobinopathies. Hematol Oncol Clin North Am. 2017 Oct;31(5):835-852. doi: 10.1016/j.hoc.2017.06.010. Review. PubMed PMID: 28895851.
• Glaser A, McColl B, Vadolas J. The therapeutic potential of genome editing for β-thalassemia. F1000Res. 2015 Dec 11;4. pii: F1000 Faculty Rev-1431. doi: 10.12688/f1000research.7087.1. eCollection 2015. Review. PubMed PMID: 26918126; PubMed Central PMCID: PMC4753996.

A double-blind randomized clinical trial compared use of a third-generation irreversible EGFR-TKI (osimertinib) versus standard therapy (gefitinib or erlotinib) to treat non small-cell lung cancer. You can read the results of this study in the New England Journal of Medicine.

Soria, J. C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K. H., ... & Okamoto, I. (2017). Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. New England Journal of Medicine.

To learn more about EGFR mutations in non small-cell lung cancer, explore additional readings from Himmelfarb Library's full-text collection:

• Li, J & Bluth MH. (2017). Pharmacogenomics and Personalized Medicine. From Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed. Elsevier, Inc.
• Shilpa J, Zhang DY, Xu R, Pincus MR & Lee, P. (2017). Molecular Genetic Pathology of Solid Tumors. From Henry's Clinical Diagnosis and Management by Laboratory Methods. 23rd ed. Elsevier, Inc.
• Wagner, H. & Langer CJ. (2016). Non-Small Cell Lung Cancer. From Clinical Radiation Oncology. 4th ed. Elsevier, Inc.

That is the question now being considered in light of a new research article in the New England Journal of Medicine in which a new gene therapy drug was given to men with hemophilia B.  After receiving the new drug, the patients were able to stop using clotting factors to treat their hemophilia.  Patients rates of bleeding also fell - from about 11 bleeding events per year to less than one bleeding event per year.  Read about the research here:

• van den Berg, H. Marijke (12/2017). A Cure for Hemophilia within Reach. The New England journal of medicine. (ISSN: 0028-4793).  Epub ahead of print.
• Porteus, Matthew (12/2017). Closing In on Treatment for Hemophilia B. The New England journal of medicine. , 377 (23), p. 2274 - 2275. doi:10.1056/NEJMe1713735 [doi]
• George, L. A., Sullivan, S. K., Giermasz, A., Rasko, J. E., Samelson-Jones, B. J., Ducore, J., ... & McGuinn, C. E. (2017). Hemophilia B gene therapy with a high-specific-activity factor IX variant. New England Journal of Medicine, 377(23), 2215-2227.  doi:10.1056/NEJMoa1708538 [doi]

• Is this drug more effective for individuals with a specific genetic profile?  
• Are some people at increased risk of a serious drug reaction from a specific drug?  
• How is pharmacogenomic information being used clinically right now?

Pharmacogenomics: Precision Medicine and Drug Response, a new CME review article from the Mayo Clinic Proceedings, explores these issues.  This article provides a brief history of pharmacogenomics, information on current clinical applications, and conceptualizes the future of pharmacogenomics.

To explore more genetics topics, check out Dr. Charles Macri's online Genetics Journal Club!

Is obesity caused by more factors than eating too much and exercising too little?

A new article in the Proceedings of the National Academy of Sciences describes a genetic variation called ankyrin-B which may cause people to gain weight.   This article by Damaris N. Lorezo and Vann Bennett demonstrates that ankyrin-B deficiency makes mice more likely to become obese with age or when fed a high-fat diet.  

Genetic link between asthma, hay fever, and eczema?

Clinicians have long know that patients who have asthma are also likely to have hay fever or eczema.  Researchers have now identified the gene variants which are responsible for this association and published their results in Nature Genetics.  To find these variants, the genomes of more than 360,000 people were analyzed and 136 positions in the genome were identified.  If an individual has inherited these genetic risk factors, that person is a higher risk of developing asthma, hay fever, and/or eczema - or all three!

Is there a genetic cause for preterm births? 

While evidence has suggested that this is true, the first study identifying specific genetic factors that exist in women with preterm deliveries was just published in the New England Journal of Medicine.  This study used data from nearly 50,000 women and identified specific genetic variations which can predict length of gestation and risk of preterm birth: