{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T22:41:44Z","timestamp":1776120104571,"version":"3.50.1"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:00:00Z","timestamp":1748908800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>High-grade serous ovarian carcinoma (HGSOC), an aggressive cancer associated with pathogenic <jats:italic>BRCA<\/jats:italic> variants, causes genomic instability and sensitivity to poly (ADP-ribose) polymerase inhibitors. Identifying pathogenic <jats:italic>BRCA<\/jats:italic> variants is crucial for the treatment of HGSOC; however, genetic testing is expensive and time-consuming. This study aimed to explore pathological features, particularly the presence of tumor-infiltrating lymphocytes (TILs), as potential surrogates to streamline patient selection for genetic testing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We retrospectively analyzed 58 cases of HGSOC with known <jats:italic>BRCA<\/jats:italic> variant profiles. Tumors were categorized as TIL-positive or TIL-negative based on the presence of &amp;gt; 40 or \u2264 40 intraepithelial lymphocytes in a single high-power field (HPF), respectively. Key pathological features, including solid, endometrioid, and transitional (SET) architecture patterns; necrosis; and mitotic activity, were evaluated within these subgroups. Statistical analyses were used to determine the associations between these features and <jats:italic>BRCA<\/jats:italic> variant status.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In TIL-negative HGSOCs, SET patterns were strongly associated with pathogenic or likely pathogenic <jats:italic>BRCA<\/jats:italic> variants (<jats:italic>p<\/jats:italic> = 0.028), emerging as the most reliable morphological marker in this group. In TIL-positive HGSOCs, low mitotic activity (\u22647 mitotic figure per 10 HPFs) was significantly correlated with pathogenic <jats:italic>BRCA<\/jats:italic> variants (<jats:italic>p<\/jats:italic> = 0.0002), underscoring its diagnostic significance. Necrosis and mitotic activity in TIL-negative cases and SET patterns in TIL-positive cases were not significantly associated with pathogenic <jats:italic>BRCA<\/jats:italic> variants. Combined analysis of both TIL subgroups diluted these associations, underscoring the significance of stratifying cases by the immune context.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The presence of TILs affects the diagnostic value of pathological features for <jats:italic>BRCA<\/jats:italic> variant status in HGSOC. Regarding pathogenic <jats:italic>BRCA<\/jats:italic> variants, SET patterns and low mitotic activity were identified as critical markers in TIL-negative tumors and TIL-positive tumors, respectively. These associations likely stem from interactions among genomic instability, immune response, and tumor growth. Our framework leverages these insights to prioritize high-risk cases for genetic testing, thereby optimizing resource allocation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The presence of TILs is critical for understanding the association between pathological features and pathogenic <jats:italic>BRCA<\/jats:italic> variants in HGSOC. To improve pathogenic <jats:italic>BRCA<\/jats:italic> variant prediction, optimize genetic testing, and guide tailored intervention, our framework integrates immune context and morphological markers. This approach is especially useful in resource-limited settings and can enhance diagnostic efficiency and clinical decision-making.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2025.1555883","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T14:42:50Z","timestamp":1748961770000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Tumor-infiltrating lymphocytes are the key determinants of pathological features associated with pathogenic BRCA variants in high-grade serous ovarian carcinoma"],"prefix":"10.3389","volume":"12","author":[{"given":"Dang H.","family":"Nguyen-Phan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tin","family":"Dang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anh N.","family":"Dang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loc T. 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