SUMMARY We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multidimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.

It is becoming increasingly evident that cancers are dependent on a number of altered molecular pathways and can develop diverse mechanisms of resistance to therapy with single agents. Therefore, combination regimens may provide the best hope for effective therapies with durable effects. Despite preclinical data to support this notion, there are many challenges to the development of targeted combinations including scientific, economic, legal, and regulatory barriers. A discussion of these challenges and identification of models and best practices are presented with intent of aiding the research community in addressing real and perceived barriers to the development of combination therapies for cancer.

Patient advocacy organizations play a major role in accelerating research and are particularly important in a disease like melanoma, for which there is an urgent need for new tools and treatments. Melanoma is a growing public health burden. In the United States alone, the incidence of melanoma has tripled over the past 30 years, and one American dies every hour from the disease. To accelerate the field, the Melanoma Research Alliance (MRA) was founded in 2007 and is now the largest private funder of melanoma research, having invested more than $48 million in innovative and translational research projects worldwide to date. This investment is bearing fruit in the recent transformation of the melanoma clinical landscape, which has brought new hope to patients and their families. Yet, even with new drugs on the market, much more needs to be done until melanoma is effectively addressed. MRA is part of a growing group of nonprofit disease research foundations collectively called "venture philanthropies" that are playing a powerful role in transforming the outlook for their disease by overcoming barriers that bog down progress, targeting key areas, and enhancing collaboration. MRA is leading an innovative agenda to accelerate efforts on behalf of patients. Our goal, while significant, is straightforward: to end suffering and death due to melanoma.

The incidence rates of sporadic early-onset colorectal cancer (EO-CRC) are increasing rapidly in the USA and globally. Birth cohort analyses strongly suggest that changes in early life exposures to known or unknown risk factors for CRC may be driving EO disease, but the etiology of EO-CRC remains poorly understood. To address the alarming rise in sporadic EO-CRC, the National Cancer Institute and National Institute of Environmental Health Sciences convened a virtual meeting that featured presentations and critical discussions from EO-CRC experts that examined emerging evidence on potential EO-CRC risk factors, mechanisms and translational opportunities in screening and treatment.