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Hypoxia increases mutational load of breast cancer cells through frameshift mutations.

ABSTRACT: Tumor hypoxia-induced downregulation of DNA repair pathways and enhanced replication stress are potential sources of genomic instability. A plethora of genetic changes such as point mutations, large deletions and duplications, microsatellite and chromosomal instability have been discovered in cells under hypoxic stress. However, the influence of hypoxia on the mutational burden of the genome is not fully understood. Here, we attempted to elucidate the DNA damage response and repair patterns under different types of hypoxic stress. In addition, we examined the pattern of mutations exclusively induced under chronic and intermittent hypoxic conditions in two breast cancer cell lines using exome sequencing. Our data indicated that hypoxic stress resulted in transcriptional downregulation of DNA repair genes which can impact the DNA repair induced during anoxic as well as reoxygenated conditions. In addition, our findings demonstrate that hypoxic conditions increased the mutational burden, characterized by an increase in frameshift insertions and deletions. The somatic mutations were random and non-recurring, as huge variations within the technical duplicates were recognized. Hypoxia also resulted in an increase in the formation of potential neoantigens in both cell lines. More importantly, these data indicate that hypoxic stress mitigates DNA damage repair pathways and causes an increase in the mutational burden of tumor cells, thereby interfering with hypoxic cancer cell immunogenicity.

SUBMITTER: Hassan Venkatesh G

PROVIDER: S-EPMC7185205 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Hypoxia increases mutational load of breast cancer cells through frameshift mutations.

Hassan Venkatesh Goutham G Bravo Pamela P Shaaban Moustafa Elsayed Walid W Amirtharaj Francis F Wojtas Bartosz B Abou Khouzam Raefa R Hussein Nawafleh Husam H Mallya Sandeep S Satyamoorthy Kapaettu K Dessen Philippe P Rosselli Filippo F Thiery Jerome J Chouaib Salem S

Oncoimmunology 20200416 1

Tumor hypoxia-induced downregulation of DNA repair pathways and enhanced replication stress are potential sources of genomic instability. A plethora of genetic changes such as point mutations, large deletions and duplications, microsatellite and chromosomal instability have been discovered in cells under hypoxic stress. However, the influence of hypoxia on the mutational burden of the genome is not fully understood. Here, we attempted to elucidate the DNA damage response and repair patterns unde ...[more]

PMID: 32363122

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Project description:Breast cancer is a complex molecular disease comprising several biological subtypes. However, daily routine diagnosis is still based on a small set of well-characterized clinico-pathological variables. Here, we try to link the two worlds of surgical pathology and multilayered molecular profiling by analyzing the relationships between clinico-pathological phenotypes and mutational loads of breast cancer. We evaluated the number of mutated genes with somatic non-silent mutations in different subgroups of breast cancer based on clinico-pathological, including immunohistochemical and tumour characteristics. The analysis was performed for a cohort of 687 primary breast cancer patients with mutational profiling, gene expression and clinico-pathological data available from The Cancer Genome Atlas (TCGA) project. The number of mutated genes was strongly positively associated with higher tumour grade (p = 1.4e-14) and with the different immunohistochemical and PAM50 molecular subtypes of breast cancer (p = 1.4e-10 and p = 4.3e-10, respectively). We observed significant associations (|R| > 0.4) between the abundance of mutated genes and expression levels of genes related to proliferation in the overall cohort and hormone receptor positive cohort, including the Recurrence Score gene signature (e.g., MYBL2 and BIRC5). Specific mutated genes (TP53, NCOR1, NF1, PTPRD and RB1) were highly significantly associated with high loads of mutated genes. Multivariate analysis for overall survival (OS) revealed a worse survival for patients with high numbers of mutated genes (hazard ratio = 4.6, 95% CI: 1.0 - 20.0, p = 0.044). Here, we report a strong association of the number of mutated genes with immunohistochemical and PAM50 subtypes and tumour grade in breast cancer. We provide evidence that specific levels of the mutational load underlie different morphological and biological phenotypes, which collectively constitute the current basis of pathological diagnosis. Our study is a step towards genomics-informed breast pathology and will provide a basis for future studies in this field bridging the gap between morphology, tumour biology and medical oncology.

Project description:Accumulating evidence indicates that a small population of cancer stem cells (CSCs) is involved in intrinsic resistance to cancer treatment. The hypoxic microenvironment is an important stem cell niche that promotes the persistence of CSCs in tumors. Our aim here was to elucidate the role of hypoxia and CSCs in the resistance to gefitinib in non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation. NSCLC cell lines, PC9 and HCC827, which express the EGFR exon 19 deletion mutations, were exposed to high concentration of gefitinib under normoxic or hypoxic conditions. Seven days after gefitinib exposure, a small fraction of viable cells were detected, and these were referred to as "gefitinib-resistant persisters" (GRPs). CD133, Oct4, Sox2, Nanog, CXCR4, and ALDH1A1-all genes involved in stemness-were highly expressed in GRPs in PC9 and HCC827 cells, and PC9 GRPs exhibited a high potential for tumorigenicity in vivo. The expression of insulin-like growth factor 1 (IGF1) was also upregulated and IGF1 receptor (IGF1R) was activated on GRPs. Importantly, hypoxic exposure significantly increased sphere formation, reflecting the self-renewal capability, and the population of CD133- and Oct4-positive GRPs. Additionally, hypoxia upregulated IGF1 expression through hypoxia-inducible factor 1α (HIF1α), and markedly promoted the activation of IGF1R on GRPs. Knockdown of IGF1 expression significantly reduced phosphorylated IGF1R-expressing GRPs under hypoxic conditions. Finally, inhibition of HIF1α or IGF1R by specific inhibitors significantly decreased the population of CD133- and Oct4-positive GRPs, which were increased by hypoxia in PC9 and HCC827 cells. Collectively, these findings suggest that hypoxia increased the population of lung CSCs resistant to gefitinib in EGFR mutation-positive NSCLC by activating IGF1R. Targeting the IGF1R pathway may be a promising strategy for overcoming gefitinib resistance in EGFR mutation-positive NSCLC induced by lung CSCs and microenvironment factors such as tumor hypoxia.

Dataset Information

Hypoxia increases mutational load of breast cancer cells through frameshift mutations.

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Hypoxia increases mutational load of breast cancer cells through frameshift mutations.

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