Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8(+) TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas.
Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8(+) TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas.
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DOI：
10.1002/path.5849
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发表时间：
2022-04
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影响因子：
--
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中科院分区：
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ARID 1A（BAF 250 a）是SWI/SNF染色质修饰复合物的一个组成部分，起着重要的肿瘤抑制作用，并被认为是几种恶性肿瘤的预后。然而，在卵巢癌中，关于其与预后、免疫应答的关系以及与临床病理特征的相关性的报道相互矛盾。我们通过结合卵巢肿瘤组织分析（OTTA）联盟，加拿大卵巢统一实验资源（COEUR），当地和合作网络的资源，收集了一系列1，623例卵巢癌相关的卵巢癌，包括1，078例类卵巢癌（ENOC）和545例透明细胞（CCOC）卵巢癌。对所有样本应用经验证的ARID 1A突变免疫组织化学替代试验。我们研究了ARID 1A缺失/突变、临床特征、结果、CD 8+肿瘤浸润淋巴细胞（CD 8 + TIL）和DNA错配修复缺陷（MMRd）之间的关系。在42%的CCOC和25%的ENOC中观察到ARID 1A丢失。我们发现ARID 1A丢失与CCOC的结局、分期、年龄或CD 8 + TIL状态之间无相关性。同样地，我们也没有发现与类神经胶质瘤病例的结果或分期相关。在ENOC中，ARID 1A丢失在年轻患者中更普遍（p=0.012），并与MMRd（p<0.001）和CD 8 + TIL（p=0.008）相关。与MMRd是ARID 1A突变的原因一致，在ENOC的一个子集中，我们还观察到ARID 1A功能丧失突变之间的关联，这是由于小插入缺失（p=0.035，相对于单核苷酸变体）。在ENOC中，ARID 1A丢失、CD 8 + TIL和年龄之间的关联似乎受到MMRd状态的混淆。尽管这一观察结果并未明确排除ARID 1A对ENOC中CD 8 + TIL浸润的影响，但鉴于目前关于MMRd的知识，似乎更可能的是，影响由超突变表型主导。这个具有一致应用的生物标志物评估的大型数据集现在为ARID 1A功能丧失突变在卵巢癌相关性卵巢癌中的患病率提供了基准，并使预后意义变得清晰。
ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1,623 endometriosis-associated ovarian carcinomas, including 1,078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TIL), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOC and 25% of ENOC. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p=0.012), and associated with MMRd (p<0.001), and presence of CD8+ TIL (p=0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOC we also observed an association between ARID1A loss-of-function mutation as a result of small indels (p=0.035, versus single nucleotide variants). In ENOC, the association between ARID1A loss, CD8+ TIL, and age, appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance.
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影响因子：
3.7
作者：
Heckl M;Schmoeckel E;Hertlein L;Rottmann M;Jeschke U;Mayr D
通讯作者：
Mayr D
日晒和上皮卵巢癌的风险。
影响因子：
2.3
作者：
Bodelon, Clara;Cushing-Haugen, Kara L.;Wicklund, Kristine G.;Doherty, Jennifer A.;Rossing, Mary Anne
通讯作者：
Rossing, Mary Anne
影响因子：
5.9
作者：
Enroth, Stefan;Berggrund, Malin;Gyllensten, Ulf
通讯作者：
Gyllensten, Ulf
DOI：
10.1097/pgp.0b013e31824c2372
发表时间：
2012-09-01
影响因子：
2.4
作者：
Bromley, Amy B.;Altman, Alon D.;Koebel, Martin
通讯作者：
Koebel, Martin
影响因子：
3.8
作者：
Garcia-Closas, Montserrat;Brinton, Louise A.;Chanock, Stephen J.
通讯作者：
Chanock, Stephen J.