Instituto de Biología Y Genética Molecular, IBGM University of Valladolid, Sanz Y Fores Street, 3, 47003, Valladolid, Spain.
Guardant Health, 505 Penobscot Dr, Redwood, CA, 94063, USA.
J Med Case Rep. 2021 Feb 19;15(1):89. doi: 10.1186/s13256-020-02589-1.
Tumor molecular screening allows categorization of molecular alterations to select the best therapeutic strategy. AT-rich interactive domain-containing 1A (ARID1A) gene mutations are present in gastric, endometrial, and clear cell ovarian tumors. Inactivation of this gene impairs mismatch repair (MMR) machinery leading to an increased mutation burden that correlates with microsatellite instability (MSI), associated with tumor-infiltrating lymphocytes and programmed death ligand 1 (PD-L1) expression. This is the first case report in lung adenocarcinoma of ARID1A gene alterations leading to sporadic MSI, through somatic mutL homolog 1 (MLH1) promoter methylation, with an MLH1 gene mutation as the second somatic hit.
A 50-year-old never-smoker Bulgarian woman, with no comorbidities and no family history of cancer, was diagnosed with metastatic lung adenocarcinoma. PD-L1 immunohistochemistry (IHC) of tissue biopsies on right groin adenopathies resulted in 30% positivity. Liquid biopsy test reported actionable alterations in ARID1A gene, rearranged during transfection (RET) gene fusions, epidermal growth factor receptor (EGFR) gene R776H mutation, breast cancer (BRCA) genes 1/2, and cyclin-dependent kinase inhibitor 2A (CDKN2A) gene mutations. The patient was treated with immunotherapy, and showed a treatment response lasting for 19 months until a new metastasis appeared at the right deltoid muscle. Genomic analysis of a sample of this metastasis confirmed PD-L1 positivity of greater than 50% with CD8 T cells expression and showed MSI with a deleterious c.298C>T (p.R100*) MLH1 gene mutation. Multiplex ligation-dependent probe amplification (MLPA) of this sample unveiled MLH1 gene promoter methylation. The MLH1 gene mutation and the MLH1 gene methylation were not present at the germline setting.
In this particular case, we show that ARID1A gene mutations with sporadic MSI due to somatic MLH1 gene promoter methylation and MLH1 gene mutation could change the prognosis and define the response to immunotherapy in a patient with lung adenocarcinoma. Comprehensive solid and liquid biopsy tests are useful to find out resistance mechanisms to immune checkpoint inhibitors. Our data encourages the development of new therapies against ARID1A mutations and epigenomic methylation when involved in MSI neoplasms.
肿瘤分子筛查可对分子改变进行分类，以选择最佳治疗策略。富含 AT 相互作用域的 1A（ARID1A）基因突变存在于胃、子宫内膜和透明细胞卵巢肿瘤中。该基因失活会损害错配修复（MMR）机制，导致突变负担增加，与微卫星不稳定性（MSI）相关，与肿瘤浸润淋巴细胞和程序性死亡配体 1（PD-L1）表达相关。这是首例肺腺癌 ARID1A 基因突变导致散发性 MSI 的病例报告，这是通过体细胞 mutL 同源物 1（MLH1）启动子甲基化引起的，MLH1 基因突变是第二个体细胞突变。
一名 50 岁的保加利亚女性，从不吸烟，无合并症，无癌症家族史，被诊断为转移性肺腺癌。右腹股沟淋巴结活检的 PD-L1 免疫组织化学（IHC）结果显示阳性率为 30%。液体活检报告 ARID1A 基因、转染时重排（RET）基因融合、表皮生长因子受体（EGFR）基因 R776H 突变、乳腺癌（BRCA）基因 1/2 和细胞周期蛋白依赖性激酶抑制剂 2A（CDKN2A）基因的可治疗改变。该患者接受免疫治疗，治疗反应持续 19 个月，直到右三角肌出现新的转移。该转移样本的基因组分析证实 CD8 T 细胞表达 PD-L1 阳性率大于 50%，且 MSI 存在有害的 c.298C>T（p.R100*）MLH1 基因突变。该样本的多重连接依赖性探针扩增（MLPA）显示 MLH1 基因启动子甲基化。MLH1 基因突变和 MLH1 基因甲基化在种系中不存在。
在本例中，我们表明 ARID1A 基因突变伴散发性 MSI 是由于体细胞 MLH1 基因启动子甲基化和 MLH1 基因突变所致，可能改变肺腺癌患者的预后并确定对免疫治疗的反应。综合实体和液体活检有助于发现免疫检查点抑制剂耐药机制。我们的数据鼓励开发针对 ARID1A 突变和涉及 MSI 肿瘤的表观遗传甲基化的新疗法。
