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Loss of heterozygosity related to TMB and TNB may predict PFS for patients with SCLC received the first line setting
Journal of Translational Medicine ( IF 7.4 ) Pub Date : 2021-09-08 , DOI: 10.1186/s12967-021-03019-6
Chenyue Zhang 1 , Kai Wang 2 , Haiyong Wang 3
Affiliation  

Genes have two alleles or copies, with one inherited from each parent. The loss of one of these gene copies, termed as loss of heterozygosity (LOH), is one of the most common genetic alterations in cancer [1]. LOH has been playing a pivotal role in cancer development [2]. For instance, LOH was found to be involved in the relapse of acute lymphoblastic leukemia [3]. LOH of human leukocyte antigen (HLA) alleles hampered the ability of major histocompatibility complex to present neoantigens, thus implicating in resistance to immune checkpoint blockade (ICB) therapy [4]. Therefore, expounding the relationship between LOH and cancer will be very helpful to guide the accurate treatment.

Small cell lung cancer (SCLC) is featured by rapid growth and tendency to metastasize, with grim prognosis and high relapse rate [5]. However, the landscape of LOH and its impact on prognosis and relapse has remained largely unknown in SCLC. Moreover, the association between LOH and immunological features has never been studied in SCLC.

A total of 178 histologically confirmed SCLC patients were collected from Shandong Cancer Hospital and Institute. This study was approved by the Ethics Committee of Shandong Cancer Hospital and Institute. All included patients in this study offered written informed consent. Whole-exome-sequencing (WES) analyses were performed to detect the of the tumor mutational burden (TMB) and tumor neoantigen burden (TNB) for SCLC patients. We have demonstrated that SCLC patients with higher LOH were associated with lower tumor mutational burden (TMB) (R square = 0.0825, P  = 0.0001; Fig. 1A). Similarly, LOH was found to be negatively associated with lower tumor neoantigen burden (TNB) (R square = 0.0726, P  = 0.0003; Fig. 1B). Since CD8 + T cells are the body’s main immunological barrier against cancer and PD-L1 expression has reported to be a biomarker for immunotherapy, we next analyzed the association between CD8 + T cell infiltration, PD-L1 expression and LOH in SCLC. CD8 + TIL density and PD-L1 expression was measured using immunohistochemistry. In addition, X-tile software was applied to determine the optimal cutoff of LOH to differentiate progression free survival (PFS) (endup point for PFS: 15th, December, 2020) [6]. LOH was divided low and high in light of the optimal cutoff. The results showed that there was no significant difference in CD8 + T cell infiltration between low-LOH and high-LOH SCLC patients (P  = 0.5796; Fig. 1C). SCLC patients with low LOH had numerically higher PD-L1 positive expression than those with high LOH (20.69% versus 10.83%; Fig. 1D). Importantly, in the LOH-low cohort, PFS was significantly prolonged compared with that in LOH-high cohort (P  = 0.0305; Fig. 1E). Moreover, multivariate Cox regression analyses were further conducted to evaluate the prognostic factors on PFS. We have found that LOH remains to be an independent factor for predicting PFS even after adjusting for factors including age, sex, smoking, family history and stage (HR, 1.574; 95% CI 1.033–2.398; P  = 0.035; Additional file 1: Table S1). Additionally, there was no significant difference in overall survival (OS) (endup point for OS: 26th, November, 2020) between LOH-low and LOH-high cohort (P  = 0.2862; Fig. 1F).

Fig. 1
figure1

The association of LOH with immune-related markers and the impact of LOH on survival. A The association between LOH and TMB for SCLC patients. B The association between LOH and TNB for SCLC patients. C The difference in CD8 + TIL infiltration between low-LOH and high-LOH in SCLC patients. D The difference in positive PD-L1 expression between low-LOH and high-LOH in SCLC patients. E The effect of LOH on PFS in SCLC patients. The cutoff for LOH is determined by X-tile. F The effect of LOH on OS in SCLC patients

Full size image

To the best of our knowledge, we are the first to analyze the association between immune-related markers including TMB, TNB, CD8 + TIL, PD-L1 and LOH for patients with SCLC. We not only demonstrated the negative association between LOH and TMB, TNB in SCLC, but also revealed that low LOH is associated with prolonged PFS. We concluded that LOH may predict PFS by negatively affecting TMB and TNB in SCLC. Our finding suggests that LOH is a very valuable benchmark that predicts PFS in SCLC. Undeniably, more clinical and translational researches are warranted for confirmation of LOH’s role in SCLC.

The data are available from the corresponding authors upon reasonable request.

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We thank for the technical support of Chenglong Zhao from Shandong Cancer Hospital for pathological analysis; we also thank for Zhenzhen Li from Berry Oncology Corporation for Bioinformatics technology support.

This study was supported jointly by Special funds for Taishan Scholars Project (Grant No. tsqn201812149), Academic promotion program of Shandong First Medical University (2019RC004).

Author notes

  1. Chenyue Zhang and Kai Wang are first authors and contributed equally to this work

Affiliations

  1. Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai Medical College, Shanghai, 200032, China

    Chenyue Zhang

  2. Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, 646000, China

    Kai Wang

  3. Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Number 440, Ji Yan Road, Jinan, 250117, China

    Haiyong Wang

Authors
  1. Chenyue ZhangView author publications

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  2. Kai WangView author publications

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  3. Haiyong WangView author publications

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Contributions

CZ performed data analysis and manuscript preparation. KW re-verified the data and polished the language. HW designed the study and revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Haiyong Wang.

Ethics approval and consent to participate

This study was approved by the ethics committee of Shandong Cancer Hospital and Institute. All included patients in this study offered written informed consent.

Consent for publication

All authors give their consent to publish this manuscript.

Competing interests

The authors declare that there is no competing interests.

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Additional file 1

: Table S1. Multivariate Cox regression analyses to evaluate the prognostic factors for PFS.

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Zhang, C., Wang, K. & Wang, H. Loss of heterozygosity related to TMB and TNB may predict PFS for patients with SCLC received the first line setting. J Transl Med 19, 385 (2021). https://doi.org/10.1186/s12967-021-03019-6

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  • DOI: https://doi.org/10.1186/s12967-021-03019-6

中文翻译：
与 TMB 和 TNB 相关的杂合性缺失可预测接受一线治疗的 SCLC 患者的 PFS

基因有两个等位基因或副本，每个等位基因都遗传一个。这些基因拷贝之一的丢失，称为杂合性丢失 (LOH)，是癌症中最常见的基因改变之一 [1]。LOH 一直在癌症发展中发挥关键作用 [2]。例如，发现 LOH 与急性淋巴细胞白血病的复发有关 [3]。人类白细胞抗原 (HLA) 等位基因的 LOH 阻碍了主要组织相容性复合体呈递新抗原的能力，从而导致对免疫检查点阻断 (ICB) 治疗的抵抗 [4]。因此，阐明LOH与癌症的关系，对指导准确治疗非常有帮助。

小细胞肺癌(small cell lung cancer, SCLC)具有生长快、易转移、预后差、复发率高等特点[5]。然而，在 SCLC 中，LOH 的情况及其对预后和复发的影响在很大程度上仍然未知。此外，从未在 SCLC 中研究 LOH 与免疫学特征之间的关联。

从山东省肿瘤医院和研究所收集了178例经组织学证实的SCLC患者。本研究经山东省肿瘤医院及研究所伦理委员会批准。本研究中所有包括的患者都提供了书面知情同意书。进行全外显子组测序（WES）分析以检测SCLC患者的肿瘤突变负荷（TMB）和肿瘤新抗原负荷（TNB）。我们已经证明，具有较高 LOH 的 SCLC 患者与较低的肿瘤突变负荷 (TMB) 相关（R 方 = 0.0825，P  = 0.0001；图 1A）。同样，发现 LOH 与较低的肿瘤新抗原负荷 (TNB) 呈负相关（R 平方 = 0.0726，P = 0.0003; 图 1B)。由于 CD8 + T 细胞是身体对抗癌症的主要免疫屏障，并且据报道 PD-L1 表达是免疫治疗的生物标志物，我们接下来分析了 SCLC 中 CD8 + T 细胞浸润、PD-L1 表达和 LOH 之间的关联。使用免疫组织化学测量 CD8 + TIL 密度和 PD-L1 表达。此外，应用 X-tile 软件来确定 LOH 的最佳截止值，以区分无进展生存期 (PFS)（PFS 的终点：2020 年 12 月 15 日）[6]。根据最佳截止值，LOH 分为低和高。结果显示，低LOH和高LOH SCLC患者CD8+T细胞浸润无显着差异（P = 0.5796; 图 1C)。LOH 低的 SCLC 患者的 PD-L1 阳性表达在数值上高于 LOH 高的患者（20.69% 对 10.83%；图 1D）。重要的是，在 LOH 低队列中，与 LOH 高队列相比，PFS 显着延长（P  = 0.0305；图 1E）。此外，进一步进行多变量 Cox 回归分析以评估 PFS 的预后因素。我们发现，即使在调整了年龄、性别、吸烟、家族史和分期等因素后，LOH 仍然是预测 PFS 的独立因素（HR，1.574；95% CI 1.033–2.398；P  = 0.035；附加文件 1：表 S1)。此外，LOH-low 和 LOH-high 队列的总生存期 (OS)（OS 终点：2020 年 11 月 26 日）没有显着差异（P  = 0.2862；图 1F）。

图。1
图1

LOH 与免疫相关标志物的关联以及 LOH 对生存的影响。A SCLC 患者 LOH 和 TMB 之间的关联。B SCLC 患者 LOH 和 TNB 之间的关联。C SCLC 患者中低 LOH 和高 LOH 之间 CD8 + TIL 浸润的差异。D SCLC 患者低-LOH 和高-LOH 之间PD-L1 阳性表达的差异。E LOH 对 SCLC 患者 PFS 的影响。LOH 的截止值由 X-tile 确定。F LOH对SCLC患者OS的影响

全尺寸图片

据我们所知，我们是第一个分析免疫相关标志物（包括 TMB、TNB、CD8 + TIL、PD-L1 和 LOH）与 SCLC 患者之间关联的人。我们不仅证明了 SCLC 中 LOH 与 TMB、TNB 之间的负相关，而且还揭示了低 LOH 与延长的 PFS 相关。我们得出结论，LOH 可能通过对 SCLC 中的 TMB 和 TNB 产生负面影响来预测 PFS。我们的发现表明 LOH 是一个非常有价值的基准，可以预测 SCLC 的 PFS。不可否认，需要更多的临床和转化研究来确认 LOH 在 SCLC 中的作用。

数据可根据合理要求从通讯作者处获得。

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    文章 谷歌学术

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下载参考

感谢山东省肿瘤医院赵成龙病理分析的技术支持；我们还要感谢来自 Berry Oncology Corporation 的 Jinzhen Li 对生物信息学技术的支持。

本研究得到山东第一医科大学学术促进计划（2019RC004）泰山学者项目专项资金（批准号：tsqn201812149）的共同支持。

作者笔记

  1. 张晨悦和王凯是第一作者，对这项工作有同等贡献

隶属关系

  1. 上海医学院复旦大学附属肿瘤医院综合治疗教研室，上海 200032

    张晨悦

  2. 西南医科大学临床前医学研究中心表观遗传与肿瘤学重点实验室, 泸州 646000

    王凯

  3. 山东省第一医科大学、山东省医学科学院山东省肿瘤医院及研究所肿瘤内科，济南市济延路440号，250117

    王海勇

作者
  1. 张晨悦查看作者出版物

    您也可以在PubMed Google Scholar中搜索此作者 

  2. 王凯查看作者出版物

    您也可以在PubMed Google Scholar中搜索此作者 

  3. 王海勇查看作者出版物

    您也可以在PubMed Google Scholar中搜索此作者 

贡献

CZ 进行了数据分析和手稿准备。KW 重新验证了数据并润色了语言。HW 设计了这项研究并修改了手稿。所有作者阅读并认可的终稿。

通讯作者

联系王海勇。

伦理批准和同意参与

本研究经山东省肿瘤医院及研究所伦理委员会批准。本研究中所有包括的患者都提供了书面知情同意书。

同意发表

所有作者都同意发表这份手稿。

利益争夺

作者声明不存在相互竞争的利益。

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Springer Nature 对已发布地图和机构附属机构中的管辖权主张保持中立。

附加文件 1

：表S1。多变量 Cox 回归分析以评估 PFS 的预后因素。

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Zhang, C.、Wang, K. 和 Wang, H. 与 TMB 和 TNB 相关的杂合性丢失可能预测接受一线设置的 SCLC 患者的 PFS。J Transl Med 19, 385 (2021)。https://doi.org/10.1186/s12967-021-03019-6

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  • DOI : https://doi.org/10.1186/s12967-021-03019-6
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