Using of Big Data to Estimate Prevalence of Defective DNA Repair Variants in the US Interview with:

Kenneth H. Kraemer,M.D.
Chief DNA Repair Section
Laboratory of Cancer Biology and Genetics, Center for Cancer Research
National Cancer Institute  What is the background for this study?

Response: At the National Cancer Institute, we have been examining patients with xeroderma pigmentosum (XP), a rare, recessively inherited, cancer-prone disease for many years. Therefore, with the increasing use of exome sequencing, we decided to see how closely”big data” corresponded with our clinical observations. What are the main findings?

Response: Patients with XP have defective DNA repair and more than a 10,000-fold increased risk of skin cancer.  Based on the literature and our clinical observations, we estimate that there are about 300 XP patients in the US.  However, after looking at 3 large databases that included more than 200,000 alleles, we were surprised to find a relatively high frequency of XP associated variants. We took a closer look a tthese variants and realized that 2 alone had frequencies estimating that ther eshould be more than 8000 people with XP in the US with these mutations. Yet only 4 individuals have been clinically identified. What should readers take away from your report?

Response: We want to highlight two main points from this work.

First,the high frequency of XP mutations compared to the low prevalence of clinical XP might suggest that mutations in known DNA repair genes may contribute to the high frequency of skin cancers in the general population and/or unexplained late onset neurodegeneration. Alternatively, our understanding of the severity of the features associated with these mutations may not be correct.  
Secondly, clinicians should approach large genomic databases with caution when trying to correlate genetic variants with prevalence of disease risk. This caution is especially relevant with prenatal testing and identifying disease-associated mutations that may never be expressed. What recommendations do you have for future research as a result of this work?

Response: It is important to follow-up with patients who might have genetic abnormalities to determine whether they will develop any clinical manifestations and what those manifestations might be. Among different people, there may be a wide spectrum of clinical manifestation associated with the same disease-associated mutations. This may be due to many factors such as other modifying genes and/or environmental influences. Having clinical information to accompany the genomic data can yield a deeper understanding of the spectrum of clinical manifestations of variants and how they could be associated with expression of the disease.

This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and Division of Cancer Epidemiology and Genetics.


Pugh J, Khan SG, Tamura D, et al.Use of Big Data to Estimate Prevalence of Defective DNA Repair Variants in the US Population. JAMA Dermatol. Published online December 05,2018. doi:10.1001/jamadermatol.2018.4473

[wysija_form id=”3″]


The information on is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.

Last Updated on December 11, 2018 by Marie Benz MD FAAD