Biased Influences of Low Tumor Purity on Mutation Detection in Cancer.

Shanshan Wang,Zheng Guo,Jun Cheng,Haidan Yan,Lu Ao,Zhangxiang Zhao,Jun He,Qingzhou Guan,Jing Li

doi:10.3389/fmolb.2020.533196

Shanshan Wang, Zheng Guo + Show 7 more

Open Access

https://doi.org/10.3389/fmolb.2020.533196

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Abstract

The non-cancerous components in tumor tissues, e.g., infiltrating stromal cells and immune cells, dilute tumor purity and might confound genomic mutation profile analyses and the identification of pathological biomarkers. It is necessary to systematically evaluate the influence of tumor purity. Here, using public gastric cancer samples from The Cancer Genome Atlas (TCGA), we firstly showed that numbers of mutation, separately called by four algorithms, were significant positively correlated with tumor purities (all p < 0.05, Spearman rank correlation). Similar results were also observed in other nine cancers from TCGA. Notably, the result was further confirmed by six in-house samples from two gastric cancer patients and five in-house samples from two colorectal cancer patients with different tumor purities. Furthermore, the metastasis mechanism of gastric cancer may be incorrectly characterized as numbers of mutation and tumor purities of 248 lymph node metastatic (N + M0) samples were both significantly lower than those of 121 non-metastatic (N0M0) samples (p < 0.05, Wilcoxon rank-sum test). Similar phenomena were also observed that tumor purities could confound the analysis of histological subtypes of cancer and the identification of microsatellite instability status (MSI) in both gastric and colon cancer. Finally, we suggested that the higher tumor purity, such as above 70%, rather than 60%, could be better to meet the requirement of mutation calling. In conclusion, the influence of tumor purity on the genomic mutation profile and pathological analyses should be fully considered in the further study.

Highlights

Somatic mutation is accumulated during tumor development, which is commonly believed to play an important role in revealing the mechanism of carcinogenesis (Stratton et al, 2009; Stratton, 2011; Nik-Zainal et al, 2012)
The tumor purity of about 72% gastric cancers were higher than 70%
According to the at least 60% of tumor purity required in most researches, we firstly removed the gastric cancer samples with tumor purity less than 60%, and observed that numbers of mutation called by four algorithms were still significant positively correlated with tumor purities (p < 0.05, Table 6)

Summary

Introduction

Somatic mutation is accumulated during tumor development, which is commonly believed to play an important role in revealing the mechanism of carcinogenesis (Stratton et al, 2009; Stratton, 2011; Nik-Zainal et al, 2012). Through sequencing analysis of cancer genomes, considerable advancements have been made in identifying cancer genes with “driver” mutation, such as TP53 (Moon et al, 2019), KRAS (Polom et al, 2019), BRAF (Yang et al, 2018a), EGFR (Paez et al, 2004), and PIK3CA (Harada et al, 2016). They provide insights into understand cancer development, find targets for therapeutic intervention (Alexandrov et al, 2013a,b) and develop diagnostic biomarkers. Various tumor purities might affect mutation detections through disturbed the numbers of mutated read (Raphael et al, 2014), and affect the biological interpretations of genomic analyses (Aran et al, 2015)

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