Kanetsky Lab
Kanetsky Lab
Incidence rates of skins cancers, including melanoma, squamous cell carcinoma, and basal cell carcinoma are on the rise in the United States, including among Hispanic/Latinos (H/L). The practice of primary prevention (e.g., sun avoidance) and secondary prevention (e.g., self-examination) can reduce the burden of morbidity and mortality of these skin cancers, but skin cancer prevention activities are poorly practiced by many in the United States.
Inherited variation at the melanocortin-1 receptor (MC1R) locus is a robust marker of skin cancer risk. Disease risk associated with MC1R variants is often stronger in individuals without traditional clinical risk phenotypes, for example individuals with dark hair color, scant freckles and who do not easily burn. The Kanetsky research team has completed two intervention trials to determine whether knowledge and feedback of MC1R genotype can promote risk reduction behaviors and early detection of skin cancers. For these studies, participants were randomized to receive health education materials by mail containing generic information about skin cancer risk, risk reduction and early detection (control arm) or precision prevention information about skin cancer risk, risk reduction, and early detection anchored in results from MC1R genotyping (intervention arm).
Consistent with our hypothesis, we found that individuals who carry higher risk MC1R variants and who received precision prevention information showed improvement in risk reduction and early detection behaviors for skin cancer over the course of the study. Also consistent with our hypothesis, we did not find behavior changes—or worsening of prevention behaviors—among individuals who carry average-risk MC1R variants and who received precision prevention materials. Interestingly, we also found changes in some primary prevention activities in young children of adult participants who carry higher risk MC1R variants. Participants in both trials found the educational materials to be believable and clear. We continue to analyze our data to produce additional findings supporting the potential to translate information on inherited genetic variation into public health and clinical practice.
Immune checkpoint blockade (ICB) therapy can help reinstate the body’s natural anti-tumor immune response otherwise hijacked during carcinogenesis. ICB has improved disease progression and survival outcomes in patients with cutaneous cancers, however, the benefit of ICB therapy is not universal. Physical activity has many positive health benefits, including improvement in cancer outcomes. Even a single bout of moderate-intensity exercise can increase the number of circulating white blood cells for up to 24 hours post-activity, and this lymphocyte boost is thought to heighten immune surveillance and regulation. However, information on how exercise exerts this benefit in cancer patients is limited, as virtually all data are from preclinical models. Although exercise can have profound effects on immune cell responses, no data exists linking exercise to immune response or clinical response in patients undergoing ICB therapy.
This pilot feasibility study will provide crucial data to address this knowledge gap. We hypothesize that temporally coupling a series of acute exercise bouts with the administration of ICB therapy will augment the effectiveness of this therapy, resulting in elevated tumor immune biomarkers and enhanced outcomes for patients. Our study seeks to (1) determine the acceptability and feasibility of implementing a day-of-infusion exercise intervention trial among patients with cutaneous cancers, including melanoma, squamous cell carcinoma, and Merkel cell carcinoma, scheduled to receive adjuvant or neoadjuvant ICB therapy, and (2) obtain preliminary data on the impact of a day-of-therapy exercise intervention on clinical outcomes and blood immune cell responses and on associations between blood immune cell responses and outcomes.
Skin cancers are an ideal starting point for precision prevention because they are the most frequently diagnosed type of cancer, the major environmental risk factor is ultraviolet light (UV), exposure to UV leaves telltale signature changes in skin cells, and skin cells are readily accessible. This project relies on a non-scarring surfactant-based skin sampling method to obtain multiple samples of skin cells from participants, including from the location of the skin cancer and other non-diseased areas on the body. "Genomic dosimeters" of UV damage in collected skin cells are measured using novel methodologies.
This study seeks to i) adapt the non-scarring sampling methodology to small samples of human skin, ii) determine how mutations in genomic dosimeters in non-diseased skin vary with UV exposure, and iii) construct prediction models of the incidence of melanoma and squamous cell carcinoma based on the genomic dosimeter mutation level in sun-exposed normal skin. The long-term goal of the project is to establish a robust route to skin cancer precision prevention using UV biological signatures.
Immunotherapies, including ipilimumab and nivolumab, have resulted in substantial improvements in the outcomes of patients with advanced melanoma. Like many treatments, not all patients respond, and some patients develop side effects. To maximize the clinical utility of these immunotherapies, we need to determine those patients most likely to respond to therapy and those at increased risk for developing side effects. However, few markers of response or development of side effect have been established. Multiple lines of evidence suggest there may be inherited genetic variants associated with response and side effects.
To identify informative inherited genetic markers, we have partnered with Bristol-Myers Squibb and identified patients treated on clinical trials with ipilimumab alone, nivolumab alone, or ipilimumab-nivolumab combination therapy. Using an unbiased approach to examine the whole genome to discover genetic markers associated with our outcomes of interest, we will determine the association of inherited variation with side effects and overall survival. The long-term goal of this work is to identify inherited variation that can inform clinical decision making for patients treated with ipilimumab and nivolumab, either as mono- or combination therapy.
The Testicular Cancer Consortium (TECAC) is an international collaborative group whose goal is to understand the genetic susceptibility to testicular germ cell tumors (TGCT). The incidence of TGCT is highest among men of European ancestry and the most common cancer affecting men aged 15-45. TECAC and its members have conducted successful genome-wide association studies (GWAS) of TGCT, and finding have revealed the critical role of genetic variation affecting essential pathways of male germ cell development and maturation, sex determination, chromosomal segregation, and DNA maintenance in TGCT susceptibility.
We currently are completing additional work to deepen our discovery of inherited variation of susceptibility to TGCT, including identifying rare and common variants using whole exome approaches followed by independent validation, conducting a transcriptome-wide association study (TWAS) using results from an updated GWAS of TGCT, and performing web-bench functional analysis on selected and prioritized top loci/genes. We anticipate our findings will lead to further ground-breaking insights into the biology and genetic etiology of TGCT and will provide data needed to identify men at greatest need for surveillance, the optimal way to decrease serious TGCT treatment-related morbidity.