CRISPR/Cas9-Mediated Genomic Editing: Implications for Engineering an Animal Model of Breast Implant-Associated Anaplastic Large Cell Lymphoma

We read with great interest the review on genomic editing by Roh and colleagues.¹ In their article, the authors summarize the technology surrounding clustered regularly interspaced short palindromic repeats-associated 9 (CRISPR-Cas9) genomic editing and suggest novel and innovative ideas for its application to plastic surgery. One application of genomic editing that warrants consideration and discussion is the potential use of CRISPR-Cas9 to generate a mouse model of breast implant associated-anaplastic large cell lymphoma (BIA-ALCL).

BIA-ALCL is a rare, but potentially lethal cancer of the immune system that is associated with the receipt of textured-surface breast implants.² To date, nearly 500 cases have been reported worldwide which has resulted in 16 deaths. Current BIA-ALCL research has largely focused on the relentless interrogation of clinical specimens which has led to important discoveries and the generation of novel hypotheses regarding disease pathogenesis. Recent genomic work has led to discovery of somatic oncogenic mutations in the Janus kinase/signal transducer and activator of transcription factor three (JAK/STAT3) pathway which is thought to be a major genetic risk factor for the devolvement of BIA-ALCL. Yet, the lack of a basic science model of BIA-ALCL continues to hinder hypothesis testing and the development of such a model remains a challenge. As such, the molecular mechanisms responsible for the pathogenesis and the role oncogenic JAK/STAT3 mutations play in BIA-ALCL remain largely unknown. Thus, the development of a genetically susceptible model of BIA-ALCL is needed.

CRISPR-Cas9 genomic editing has revolutionized cancer research and been used extensively for cancer modeling.³ In combination with high throughput genomic sequencing, CRISPR technology has been used to create tissue-specific point mutations in proto-oncogenes in order to study tumor biology in animal models. With regard to developing an animal model of BIA-ALCL, an intriguing and novel approach would be to utilize CRISPR technology to in order to engineer a genetically susceptible model of the disease. This could be accomplished by using a viral vector to deliver the CRIPSR-Cas9 system to the capsule forming around a textured-surface breast implant within a mouse model in order to create a somatic, JAK/STAT3 oncogenic mutation within the capsule itself. Similar in vivo approaches have been used successfully in murine models of cancer using lung, brain, and blood to recapitulate tumors. Theoretically, such a model may be capable of inducing BIA-ALCL tumorigenesis under the right test conditions in combination with other known risk factors (e.g. textured-surface implant, bacterial inoculation, time, particulate matter, etc.). Certainly, this should be an area of future study.

CRISPR-mediated genomic editing promises much in the way of scientific discovery and its potential transform the field of plastic surgery is broad and intriguing.⁴ The use of CRIPSR to genetically engineer an animal model of BIA-ALCL could have profound implications for advancing our knowledge of the biology of this disease and may provide novel insight into the malignant transformation and progression of BIA-ALCL; further investigation in this area is warranted. The authors are to be commended for bringing genomic engineering to the forefront of plastic and reconstructive surgery.