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Tumor genomic properties play a crucial role in the interaction with the immune system and have been widely explored in metastatic melanoma, but are less understood in the primary context across melanoma subtypes. Persistent tumor mutational burden (pTMB) has been proposed as an enhanced proxy of neoantigenicity in metastatic melanoma compared to standard TMB, but its role in primary disease is not known.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study utilised a cohort of 178 predominantly primary melanomas (cutaneous non-acral:\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200969, acral:\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200936, mucosal:\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200973) with available whole-genome sequencing (WGS,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009127) to measure TMB, pTMB, aneuploidy and loss of heterozygosity, as well as multiplexed immunohistochemistry (mIHC,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009140) to identify intratumoral T cells (CD3\u2009+\u2009, CD8\u2009+\u2009, CD45RO\u2009+\u2009&amp; CD103\u2009+), B cells (CD20\u2009+), dendritic cells (CD11c\u2009+), macrophages (CD68\u2009+) and PD-L1\u2009+\u2009cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Whilst pTMB is mostly contributed by mutations present in multiple copies across primary melanoma subtypes, distinct families of clonal pTMB capture relationships with CD8\u2009+\u2009T cells and CD8\u2009+\u2009CD103\u2009+\u2009T cells across subtypes not captured by clonal standard TMB. Clonal single-copy pTMB was positively associated with elevated CD8\u2009+\u2009T cell (\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.003) and CD8\u2009+\u2009CD103\u2009+\u2009T cell infiltration (\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.008) in cutaneous melanomas. In contrast, clonal multiple-copy pTMB was positively associated with elevated CD8\u2009+\u2009CD103\u2009+\u2009T cell infiltration in acral (\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.048) and mucosal (\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.049) melanomas. Cutaneous primary melanomas had greater proportions of CD8\u2009+\u2009T cells (\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.009) and CD8\u2009+\u2009CD103\u2009+\u2009T cells (\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.0002) compared to mucosal melanomas. In turn, CD8\u2009+\u2009T cell infiltration was associated with absence of lymphatic invasion (\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.003), and negatively associated with tumor mitotic rate (\n                      <jats:italic>p\u2009=<\/jats:italic>\n                      \u20090.049) in cutaneous melanomas, indicative of less aggressive disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Primary melanoma subtypes present significant differences in their immune and genomic landscapes, as well as their interactions. Distinct measures of pTMB carry added value compared to standard TMB for identification of tumour-immune associations across primary melanoma subtypes. Our findings indicate that pTMB is a relevant neoantigenicity marker in primary melanoma with the potential to modulate immune infiltration, leading to more aggressive disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-026-01673-3","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T02:07:08Z","timestamp":1779761228000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Enhanced measures of neoantigenicity capture unique tumor-immune interactions across primary melanoma subtypes"],"prefix":"10.1186","volume":"18","author":[{"given":"Eva R.","family":"Shteinman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace H.","family":"Attrill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel G.","family":"Maher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran","family":"Gnana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkateswar","family":"Addala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhe","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umaimainthan","family":"Palendira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan W.","family":"Conway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Colebatch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Waddell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas K.","family":"Hayward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John V.","family":"Pearson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina V.","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Scolyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"Wilmott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismael A.","family":"Vergara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"issue":"4","key":"1673_CR1","doi-asserted-by":"publisher","first-page":"500","DOI":"10.5858\/arpa.2019-0561-RA","volume":"144","author":"DE Elder","year":"2020","unstructured":"Elder DE, Bastian BC, Cree IA, Massi D, Scolyer RA. 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All patients gave written informed consent, and the study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Human Research Ethics Committee of Sydney Local Health District RPA Zone Human Research Ethics Committee (protocol no. X15-0454 and HREC\/11\/RPAH\/444).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"N.W., and J.V.P. are co-founders of genomiQa. G.V.L. is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Immunocore, Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. 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