miRNA Profiling in Malignant Melanoma: Making “Australia’s National Cancer” Obsolete.

Australia is a sun-worshipping country, the world capital for beautiful beaches, athletic surfers, cute marsupials, and the occasional weird-looking animal.

But it is also the capital for something less pleasant: skin cancer. In fact, at least two in three Australians will be diagnosed with skin cancer by the time they are 70. Skin cancer accounts for over 80% of all new cases of cancer diagnosed each year. Data analyzed between 1968 and 2017 for Australia’s top five cancers —colorectal, prostate, breast, lung, and melanoma— showed a downward mortality trend for the first four cancers, whereas melanoma’s death rate doubled in the past five decades.

When diagnosed early, the cure is simple and inexpensive, and yet it remains the leading cause of cancer death for young Australians. Inconsistent guidelines on screening and subjective diagnostic methods have failed to reduce the mortality rate by misdiagnosing up to 1 in 6 melanomas, thus giving the cancer time to spread before proper treatment is given. The challenge is not only an early diagnosis, but an accurate one as well. A study of over 100,000 skin biopsy diagnoses conducted in the United States in 2017 exposed a concerning lack of reproducibility and accuracy in the pathology reports: the study found 45% of the diagnoses differed between two pathologists, 48% in a panel of pathologists and 33% different diagnosis from the same pathologist (Elmore et al). Clearly, this is not just an Australian problem.

These findings underline the necessity to develop tools using biomarkers to support pathologists’ visual assessments. This is where Dr. Ryan Van Laar, Founder & CEO of Geneseq Biosciences and the NanoString nCounter micro RNA (miRNA) Expression Assay come into play.

miRNAs are a class of small regulatory non-protein-coding RNAs present both inside and outside melanoma cells and have strong tissue and disease specificity (Leidinger et al). Skincancer originates in the epidermis and becomes metastatic after invasion into the dermis. In melanoma, in situ normal skin cells became malignant by turning into primary melanoma cells (Stage 1). In a transition mechanism controlled by miRNAs, the fibroblasts surrounding the cancer tissue are recruited and turned into what are called “cancer-associated fibroblasts”. This allows melanoma cells to reach the blood stream and metastasize in other tissues (Stages 3 and 4) (Dror et al). Considering that the survival rate of melanoma in situ in Stage 1 is close to 100% while at Stage 4 it can be as low as 10%, understanding and characterizing how this transition is regulated by miRNA may lead to of the discovery of biomarkers useful in diagnostic and prognostic assays.

To this end, Dr. Van Laar and colleagues created a database of circulating miRNA expression profiles of individuals with and without melanoma by testing biopsies and plasma samples on the multiplexed NanoString nCounter miRNA V3 Assay, an assay that detects 800 human miRNAs. A classification algorithm was trained on these data and independently validated on multiple previously published miRNA data sets. The team found 38 circulating microRNAs —MEL38— that had biologically and statistically significant differences between melanoma and healthy control samples. MEL38 exhibits disease state specificity and robustness to platform and specimen-type variation.

Seeing its potential to become an objective diagnostic biomarker and improve the precision and accuracy of melanoma detection and monitoring, Dr. Van Laar, in partnership with one of Australian’s largest pathology companies, started analytical and clinical validation studies to prove the clinical utility of the test.

In this webinar, Dr. Van Laar walks us through the stages of his journey into the discovery of exciting cancer biomarkers, obtained thank to the robustness, ease of use, and reliability of the NanoString nCounter technology.

References:

Elmore JG et al, BMJ. 2017 Jun 28;357:j2813. doi: 10.1136/bmj.j2813.

Leidinger et al, BMC Cancer 10: 262.

Dror S et al, Nat Cell Biol. 2016 Sep;18(9):1006-17. doi: 10.1038/ncb3399.

Van Laar R et al, Br J Cancer. 2018 Mar 20;118(6):857-866. doi: 10.1038/bjc.2017.477.

Van Laar R et al, PLoS One. 2019 Feb 5;14(2):e0211504. doi: 10.1371/journal.pone.0211504.