CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：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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ARID1A（BAF250a）是SWI/SNF染色质修饰复合物的一个组分，发挥重要的抑癌作用，并被认为在多种恶性肿瘤中具有预后意义。
然而，在卵巢癌中，关于其与预后、免疫反应的关系以及与临床病理特征的相关性，报道存在矛盾。我们通过整合卵巢肿瘤组织分析（OTTA）联盟、加拿大卵巢统一实验资源（COEUR）、本地及协作网络的资源，组建了一个包含1623例子宫内膜异位症相关卵巢癌的系列，其中包括1078例子宫内膜样卵巢癌（ENOC）和545例透明细胞卵巢癌（CCOC）。对所有样本应用了经过验证的ARID1A突变免疫组化替代检测。
我们研究了ARID1A缺失/突变、临床特征、预后、CD8+TIL（肿瘤浸润淋巴细胞）（CD8+TILs）以及DNA错配修复缺陷（MMRd）之间的关联。在42%的CCOC和25%的ENOC中观察到ARID1A缺失。在CCOC中，我们未发现ARID1A缺失与预后、分期、年龄或CD8+TIL状态之间存在关联。同样，在子宫内膜样病例中，我们未发现与预后或分期的关联。在ENOC中，ARID1A缺失在较年轻患者中更为普遍（p=0.012），并与MMRd（p<0.001）及CD8+TILs的存在（p=0.008）相关。与MMRd是ARID1A突变的原因相一致，在一部分ENOC中，我们还观察到与小插入缺失导致的ARID1A功能丧失突变相关（p=0.035，相对于单核苷酸变异）。在ENOC中，ARID1A缺失、CD8+TILs和年龄之间的关联似乎受到MMRd状态的混杂影响。尽管这一观察并未明确排除ARID1A对ENOC中CD8 + TIL浸润的影响，但鉴于目前对MMRd的认识，似乎更可能是由超突变表型主导效应。这个大型数据集采用一致的生物标志物评估，现在为子宫内膜异位症相关卵巢癌中ARID1A功能丧失突变的患病率提供了基准，并明确了其预后意义。2021年大不列颠和爱尔兰病理学会。
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 1623 endometriosis-associated ovarian carcinomas, including 1078 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 + TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs.
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 was associated with MMRd (p < 0. 001) and the presence of CD8 + TILs (p = 0. 008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss-of-function mutation as a result of small indels (p = 0. 035, versus single nucleotide variants).
In ENOC, the association with ARID1A loss, CD8 + TILs, 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. 2021 The Pathological Society of Great Britain and Ireland.
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