Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy

Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also show that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorises patients into four immune clusters correlated with survival. The immune suppressed cluster is associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster is associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5, CD8A, and NKG7. The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials.Marjan M. Naeini, Felicity Newell, LaurenG. Aoude, Vanessa F. Bonazzi, Kalpana Patel, Guy Lampe, Lambros T. Koufariotis, Vanessa Lakis, Venkateswar Addala, Olga Kondrashova, Rebecca L. Johnston, Sowmya Sharma, Sandra Brosda, Oliver Holmes, Conrad Leonard, Scott Wood, Qinying Xu, Janine Thomas, Euan Walpole, G. Tao Mai, Stephen P. Ackland, Jarad Martin, Matthew Burge, Robert Finch, Christos S. Karapetis, Jenny Shannon, Louise Nott, Robert Bohmer, Kate Wilson, Elizabeth Barnes, John R. Zalcberg, B. Mark Smithers, John Simes, Timothy Price, Val Gebski, Katia Nones, David I. Watson, John V. Pearson, Andrew P. Barbour, Nicola Waddel

Melanomas of unknown primary have a mutation profile consistent with cutaneous sun-exposed melanoma

Summary: Melanoma of unknown primary (MUP) is an uncommon phenomenon whereby patients present with metastatic disease without an evident primary site. To determine their likely site of origin, we combined exome sequencing from 33 MUPs to assess the total rate of somatic mutations and degree of UV mutagenesis. An independent cohort of 91 archival MUPs was also screened for 46 hot spot mutations highly prevalent in melanoma including BRAF, NRAS, KIT, GNAQ, and GNA11. Results showed that the majority of MUPs exhibited high somatic mutation rates, high ratios of C>T/G>A transitions, and a high rate of BRAF (45 of 101, 45%) and NRAS (32 of 101, 32%) mutations, collectively indicating a mutation profile consistent with cutaneous sun-exposed melanomas. These data suggest that a significant proportion of MUPs arise from regressed or unrecognized primary cutaneous melanomas or arise de novo in lymph nodes from nevus cells that have migrated from the skin

POT1 loss-of-function variants predispose to familial melanoma

Dermatology-oncolog

Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma

Dermatology-oncolog