Conjunctival melanoma (CM) is a rare but aggressive cancer. Over the past decade, molecular studies using rapidly advancing technologies have increasingly improved our understanding of CM genetics. CMs are mainly characterized by dysregulated MAPK and PI3K/AKT/mTOR pathways, driven by commonly mutated (BRAF, NRAS, NF1) or less commonly mutated (KIT, PTEN) genes. Another group of genes frequently mutated in CMs include TERT and ATRX, with known roles in telomere maintenance and chromatin remodeling/epigenetic regulation. Uveal melanoma-related genes (BAP1, SF3B1, GNAQ/11) can also be mutated in CMs, albeit infrequently. Additional CM-related mutated genes have increasingly been identified using more comprehensive genetic analyses, awaiting further confirmation in additional/larger studies. As a tumor arising in a partly sun-exposed mucosal tissue, CM exhibits a distinct genomic profile, including the frequent presence of an ultraviolet (UV) signature (and high mutational load) and also the common occurrence of large structural variations (distributed across the genome) in addition to specific gene mutations. The knowledge gained from CM genetic studies to date has led to new therapeutic avenues, including the use of targeted and/or immuno-therapies with promising outcomes in several cases. Accordingly, the implementation of tumor genetic testing into the routine clinical care of CM patients holds promise to further improve and personalize their treatments. Likewise, a growing knowledge of poor prognosis-associated genetic changes in CMs (NRAS, TERT, and uveal melanoma signature mutations and chromosome 10q deletions) may ultimately guide future strategies for prognostic testing to further improve clinical outcomes (by tailoring surveillance and considering prophylactic treatments in patients with high-risk primary tumors).

The 2023 Annual Review Issue of The Journal of Pathology, Recent Advances in Pathology, contains 12 invited reviews on topics of current interest in pathology. This year, our subjects include immuno-oncology and computational pathology approaches for diagnostic and research applications in human disease. Reviews on the tissue microenvironment include the effects of apoptotic cell-derived exosomes, how understanding the tumour microenvironment predicts prognosis, and the growing appreciation of the diverse functions of fibroblast subtypes in health and disease. We also include up-to-date reviews of modern aspects of the molecular basis of malignancies, and our final review covers new knowledge of vascular and lymphatic regeneration in cardiac disease. All of the reviews contained in this issue are written by expert groups of authors selected to discuss the recent progress in their particular fields and all articles are freely available online (https://pathsocjournals.onlinelibrary.wiley.com/journal/10969896). © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BACKGROUND: Pancreatic adenocarcinoma is one of the cancers with the worst prognosis. The current treatment paradigm based on combination chemotherapy has improved survival over the last decade, but the disease is still fatal in most cases. New therapies exploiting the increasing understanding of the molecular pathology of the disease are needed. Although the disease presents with few recurrent molecular alterations, these represent opportunities for targeted treatments to be developed. However, a minority of cases are devoid of these common alterations. A description of the molecular landscape of this sub-set of pancreatic adenocarcinoma could uncover other molecular lesions present in them that could serve as therapeutic targets.
METHODS: The sub-set of pancreatic cancers without the common alterations in KRAS, TP53, CDKN2A and SMAD4 has been examined from published and publicly available pancreatic cancer cohorts for determination of their clinical and molecular characteristics. The cBioportal platform was used for this evaluation and the OncoKB knowledgebase was used for determination of the functional significance of discovered mutations.
RESULTS: About 5% to 10% of pancreatic adenocarcinomas present without the usual molecular alterations that characterize the disease. These cases tend to be genomically stable and have low prevalence of microsatellite or chromosome instability. Molecular alterations that are observed in pancreatic cancers in lower frequencies than the four most prevalent alterations, such as DNA Damage Response and epigenetic modifier mutations, are still observed in the sub-set without the common alterations and may be pathogenically relevant.
CONCLUSIONS: Despite the absence of most frequent pancreatic cancer alterations in a sub-set of pancreatic adenocarcinomas, this sub-set possesses other alterations in frequencies similar to the rest of pancreatic cancers. Putative targeting of alterations present is discussed and can serve as the basis for targeted therapies development.