Maurie Markman, MD
The advances in our technical ability to successfully interrogate the germline DNA of individuals are revolutionary. The costs associated with such efforts have declined dramatically over the past 2 decades and advances in bioinformatics have led to the development of elegant, highly reproducible, and clinically useful algorithms that can be utilized in a rapidly expanding number of settings.
For example, recently reported study findings demonstrate that whole-exome sequencing resulted in a definitive diagnoses in a quarter of an adult population (N = 92) with chronic renal disease of unknown etiology or a history of familial kidney disease or hypertension.1
Of greatest importance, the information learned through sequencing favorably influenced subsequent patient management or future familial screening efforts.1
In the cancer arena, large-scale population-based studies are revealing the impact of germline abnormalities in settings where such risk previously has not been fully appreciated. Results of a recent landmark analysis of genetic abnormalities observed across the spectrum of malignances in children, adolescents, and young adults (961 cancers evaluated) revealed the presence of “unambiguous predisposing germline variants” in 7% to 8% of the entire population.2
Again, these results point to potential therapeutic options and familial screening strategies.
Further, there remains an exciting yet untapped potential to employ germline data and knowledge about the presence of specific common, uncommon, or rare variants to correlate with clinically meaningful adverse effects of antineoplastic therapy. For example, a recent report has highlighted the value of such testing by noting the strong association between the presence of a specific genotype in the region of the Mendelian deafness genes and the development of cisplatin-associated ototoxicity.3
Knowledge of the presence of this variant prior to the use of a platinum agent might result in the selection of alternative treatment strategies, if available, or a decision to employ the lowest possible therapeutically rational cumulative dose of the agent to avoid this distressing toxicity.
Understanding Clinical Relevance
Today, the major challenge is not the discovery of differences in the genetic profiles between individuals but rather understanding the clinical relevance of particular findings. Although there are important examples of single germline abnormalities that are known to result in specific medical conditions or illnesses, it is increasingly clear that the relationship between human disease and our DNA is far more complex.
The magnitude of this issue was quite eloquently highlighted in a review article noting that, of an estimated 3 billion nucleotide pairs within the human genome, there are an estimated 3 million variants.4 Further, of the 100,000 variants suggested to be present within genes, somewhere between 1% and 5% are in or near exons of individual genes believed to be associated with disease. Finally, and of perhaps greatest importance to the point of this commentary, it is estimated that 99% of these variants are likely to be benign, with 1% or less at least partially responsible for the abnormal clinical state.4
This critically relevant effort can be characterized as an attempt to discover the proverbial needle in the haystack. In fact, considerable criticism has been directed at many published genomewide association studies that have claimed a relationship between the presence of specific variants and human disease, where critics suggest there is likely to be no meaningful biological or clinical relevance to the observations.5
The recent introduction of direct-to-consumer (DTC) genetic testing has added complexity to this discussion.6
The issue here is not the right of individuals to obtain information regarding their own genetic makeup; it is how to provide biologically and clinically valid interpretation of the data. This is a very complex discussion and includes concerns about overstating and understanding the relevance of a specific finding, providing inappropriate assurances regarding the nature of cancer- or other diseaseassociated risk, or increasing anxiety over the potential for the development of a malignancy (or other illness) where an objective assessment of currently available data simply does not support such concern.