Tumor Heterogeneity Correlates with Less Immune Response and Worse Survival in Breast Cancer Patients

McDonald, Kerry-Ann; Kawaguchi, Tsutomu; Qi, Qianya; Peng, Xuan; Asaoka, Mariko; Young, Joseph C.; Opyrchal, Mateusz; Yan, Li; Patnaik, Santosh K.; Otsuji, Eigo; Takabe, Kazuaki

doi:10.1245/s10434-019-07338-3

Cited by 140 publications

(112 citation statements)

References 48 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tumor immune microenvironment has been repeatedly demonstrated to be deeply involved in cancer progression by our group and others [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Recently, antitumor immunity was reported to correlate with increased cell cycle activity in pancreatic cancer [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection

Oshi

Newman

Tokumaru

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

Pancreatic cancer is highly mortal due to uncontrolled cell proliferation. The G2M checkpoint pathway is an essential part of the cell cycle. We hypothesized that a high G2M pathway score is associated with cell proliferation and worse survival in pancreatic cancer patients. Gene set variation analysis using the Hallmark G2M checkpoint gene set was used as a score to analyze a total of 390 human pancreatic cancer patients from 3 cohorts (TCGA, GSE62452, GSE57495). High G2M score tumors enriched other cell proliferation genes sets as well as MKI67 expression, pathological grade, and proliferation score. Independent of other prognostic factors, G2M score was predictive of disease-specific survival in pancreatic cancer. High G2M tumor was associated with high mutation rate of KRAS and TP53 and significantly enriched these pathway gene sets, as well as high infiltration of Th2 cells. High G2M score consistently associated with worse overall survival in 3 cohorts, particularly in R1/2 resection, but not in R0. High G2M tumor in R1/2 highly enriched metabolic and cellular components’ gene sets compared to R0. To our knowledge, this is the first study to use gene set variation analysis as a score to examine the clinical relevancy of the G2M pathway in pancreatic cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection

Oshi

Newman

Tokumaru

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…Tumor gene expression and corresponding clinical data for the TCGA-BRCA project were obtained from the Pan-Cancer Clinical Data Resource [39] and through cBio Cancer Genomic Portal [40], as we previously reported [41][42][43][44][45]. Data for the 1065 female patients were analyzed in the study.…”

Section: Data Of the Cancer Genome Atlas Breast Cancer Cohortmentioning

confidence: 99%

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

Oshi

Takahashi

Tokumaru

et al. 2020

IJMS

Self Cite

106

107

View full text Add to dashboard Cite

The vast majority of breast cancer death is a result of metastasis. Thus, accurate identification of patients who are likely to have metastasis is expected to improve survival. The G2M checkpoint plays a critical role in cell cycle. We hypothesized that breast cancer tumors with high activity of G2M pathway genes are more aggressive and likely to metastasize. To test this, we used the single-sample gene set variation analysis method to calculate the score for the Hallmark G2M checkpoint pathway using gene expression data of a total of 4626 samples from 12 human breast cancer cohorts. As expected, a high G2M pathway score correlated with enriched tumor expression of other cell proliferation-related gene sets. The score was significantly associated with clinical aggressive features of tumors and patient survival in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Interestingly, a high G2M score of metastasis tumors was also significantly associated with worse survival. In primary as well as metastasis tumors with high scores, the infiltration of both pro- and anti-cancerous immune cells increased. Tumor G2M score was also associated with treatment response to systemic chemotherapy in ER-positive/HER2-negative cancer, and was predictive of response to cyclin-dependent kinase inhibition therapy.

show abstract

“…Early genomic anomalies, including crucial oncogenic drivers, will therefore be present in all tumour cells and constitute clonal molecular aberrations. Acquisition of additional oncogenic drivers and passenger mutations will result in subpopulations of cancer cells with different genotypes and phenotypes, and these subclonal aberrations contribute to intratumour heterogeneity (McDonald et al , 2019). This heterogeneity is caused by somatic mutations and CNVs, as well as differences in epigenetics (Assenov et al , 2018; Easwaran et al , 2014).…”

Section: Discussionmentioning

confidence: 99%

Somatic mutations and copy number variations in breast cancers with heterogeneous HER2 amplification

et al. 2020

View full text Add to dashboard Cite

Intratumour heterogeneity fuels carcinogenesis and allows circumventing specific targeted therapies. HER2 gene amplification is associated with poor outcome in invasive breast cancer. Heterogeneous HER2 amplification has been described in 5–41% of breast cancers. Here, we investigated the genetic differences between HER2‐positive and HER2‐negative admixed breast cancer components. We performed an in‐depth analysis to explore the potential heterogeneity in the somatic mutational landscape of each individual tumour component. Formalin‐fixed, paraffin‐embedded breast cancer tissue of ten patients with at least one HER2‐negative and at least one HER2‐positive component was microdissected. Targeted next‐generation sequencing was performed using a customized 53‐gene panel. Somatic mutations and copy number variations were analysed. Overall, the tumours showed a heterogeneous distribution of 12 deletions, 9 insertions, 32 missense variants and 7 nonsense variants in 26 different genes, which are (likely) pathogenic. Three splice site alterations were identified. One patient had an EGFR copy number gain restricted to a HER2‐negative in situ component, resulting in EGFR protein overexpression. Two patients had FGFR1 copy number gains in at least one tumour component. Two patients had an 8q24 gain in at least one tumour component, resulting in a copy number increase in MYC and PVT1. One patient had a CCND1 copy number gain restricted to a HER2‐negative tumour component. No common alternative drivers were identified in the HER2‐negative tumour components. This series of 10 breast cancers with heterogeneous HER2 gene amplification illustrates that HER2 positivity is not an unconditional prerequisite for the maintenance of tumour growth. Many other molecular aberrations are likely to act as alternative or collaborative drivers. This study demonstrates that breast carcinogenesis is a dynamically evolving process characterized by a versatile somatic mutational profile, of which some genetic aberrations will be crucial for cancer progression, and others will be mere ‘passenger’ molecular anomalies.

show abstract

Tumor Heterogeneity Correlates with Less Immune Response and Worse Survival in Breast Cancer Patients

Cited by 140 publications

References 48 publications

High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection

High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

Somatic mutations and copy number variations in breast cancers with heterogeneous HER2 amplification

Contact Info

Product

Resources

About