Kaposi’s sarcoma genetic predisposition and personalized therapy

Familial Kaposi’s sarcoma and genetic whole exome analysis

Background: Kaposi’s sarcoma (KS) is a rare malignancy most commonly appearing in HIV carriers. In addition to HIV carriers, there are rare families with genetic predisposition for KS, some are Jewish descent from Morocco. Professor Moshe Schaffer identified a few such families in his service as oncologist in the Poria medical center. In collaboration with the Dangoor center for personalized medicine, we performed whole exome sequencing of eight individuals, affected and proband, from two such high-risk families, to identify the gene(s) and variant(s), responsible for this association..

“While genome sequencing may be the new kid on the block–perhaps now with a cracking voice and fuzzy facial hair–predicting phenotypes is the stuff of classical genetics, honed on the rare single-gene disorders, such as Huntington disease (HD) and cystic fibrosis (CF), which dominated the field in the last century (see Genetic Testing Timeline). “Geneticists today are portrayed as soothsayers of the future. But predictive medicine and testing has a significant history,” says Michael Hayden, professor of medical genetics at the University of British Columbia.

There was only one variation that was shared among all four affected members of one family, and among the one affected individual of the other family. Eight family members (mother and seven children, three affected) of the first family were used for the trio genetic analysis. We found three candidate KS-causing alleles. The first (likely dominant) was a variant of growth hormone gene. Growth hormone exhibits known association with breast cancers (1). This same allele was found in a second Moroccan high KS risk pedigree, where we performed exome sequencing. However, in the first pedigree, the allele was present in affected aas well as unaffected individuals. Therefore, it is likely that additional genes were involved. The second finding (likely recessive) was a gene that was already implicated in KSHV-driven KS (2,3). The gene inactivates a spectrum of g-protein coupled receptors, by phosphorylating the protein receptors, and leading them to degradation. Interestingly, the recessive nature of the variant suggest that these genes are in fact KS tumor suppressors, and play a role in KS etiology, irrespective of the KSHV infection. A third potential modifier gene was the desmoplakin DSP gene. V2138L DSP allele was present in the three affected individuals of the first family and the affected individual of the second family. DSP gene is known to affect skin morphology and dysfunctional alleles of DSP have a known skin phenotype, not observed in KS, but potentially in the presence of the other aforementioned alleles, it drives a distinct KS-risk phenotype. We are in the course of exome sequencing another trio from a third family, as well as testing the clinical implications of these findings in KS patient-derived xenografts.

The link between the findings and the Dangoor family heritage
“There is something very Jewish about implementing high throughput technologies into medical management. Jews have always resorted to creativity over the solution of brut force slave driving. In the 1970s, population-based screens to detect carriers of Tay-Sachs disease and sickle cell disease identified couples who had a 25% chance of passing on either disorder to offspring, enabling them to make informed reproductive decisions. But this echievement was obtained by an enourmous amount of research hours in the lab. Today, using genomic technology and next-generation sequencing, we can shed light on the mechanism with unbearably light effort.” Says Izhak Haviv, describing the link between the Dangoor family and personalized medicine .

  1. Shi, J., Tong, J.H. & Cai, S. GH1 T1663A polymorphism and cancer risk: a meta-analysis of case-control studies. Tumour Biol 35, 4529-38 (2014).
  2. Couty, J.P., Geras-Raaka, E., Weksler, B.B. & Gershengorn, M.C. Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor signals through multiple pathways in endothelial cells. J Biol Chem 276, 33805-11 (2001).
  3. Geras-Raaka, E. et al. Inhibition of constitutive signaling of Kaposi’s sarcoma-associated herpesvirus G protein-coupled receptor by protein kinases in mammalian cells in culture. J Exp Med 187, 801-6 (1998).