Distinct clinicopathological characteristics, genomic alteration and prognosis in breast cancer with concurrent TP53 mutation and MYC amplification

Abstract

Background Both TP53 mutation and MYC amplification indicate poor outcomes in breast cancer (BC), but the clinical values of concurrent TP53 and MYC alterations have not been well‐characterized. Methods A total of 494 BC patients diagnosed at Guangdong Provincial People's Hospital (GDPH) were retrospectively analyzed. Genomic alterations were determined using next‐generation sequencing. Survival analysis was applied to assess the effects of genetic alterations on relapse‐free survival. The prognosis was verified based on 1405 patients from METABRIC cohort. Additionally, we used logistic regression to identify the factors associated with pathological complete response (pCR) after neoadjuvant chemotherapy. Results In GDPH cohort, patients with TP53/MYC co‐alteration exhibited higher grade and stage, more positive HER2 status and higher Ki67 levels, but less luminal A subtypes. They also had more mutations in genes involved in ERBB and TGF‐β signaling pathways, as well as exclusive FANCG/CDKN2B/QKI copy number amplifications and SUFU/HIST3H3/ERCC4/JUN/BCR mutations. Concurrent TP53 and MYC alterations independently increased hazards of relapse (HR, 5.425; 95% CI: 2.019–14.579; p < 0.001). They maintained independent significance for relapse‐free (HR, 1.310; 95% CI: 1.012–1.697; p = 0.041) and overall survival (HR, 1.373; 95% CI: 1.093–1.725; p = 0.006) in METABRIC cohort. Among the 81 patients receiving chemotherapy, TP53 mutation (OR, 5.750; 95% CI: 1.553–25.776; p = 0.013) and earlier stage (OR, 0.275; 95% CI 0.088–0.788; p = 0.020) were associated with pCR, while the co‐alteration did not serve as an independent predictor ( p = 0.199). Conclusions TP53/MYC co‐alteration was associated with distinct clinicopathological and genomic features. They also conferred unfavorable prognosis in BC patients, and did not improve pCR after neoadjuvant chemotherapy.

Landscape of Genetic Mutations in Appendiceal Cancers

“…They also had more mutations in genes involved in ERBB and TGF-β signaling pathways, as well as exclusive FANCG/CDKN2B/QKI copy number amplifications and SUFU/HIST3H3/ERCC4/JUN/BCR mutations. Concurrent TP53 and MYC alterations independently increased relapse hazards, conferring unfavorable prognoses [64].…”

Acquired resistance to immunotherapy and chemoradiation in MYC amplified head and neck cancer

“…A high prevalence of alterations in the MYC oncogene is well documented in various solid malignancies, along with its association with aggressive disease and poor clinical outcomes [14][15][16] . While recurrent MYC gain-of-function mutations were found in certain human lymphomas [17][18][19] , in HNSCC, amplification appears to be the predominant genetic aberration that occurs in the MYC gene 20 , with an estimated prevalence of 12% in the HNSCC cohort of The Cancer Genome Atlas (TCGA), whereas mutations occur in only a small subset (1.2%) of patients 21 .…”