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Updated: Jun 10, 2025
Immunofluorescence Imaging of DNA Damage and Repair Foci in Human Colon Cancer Cells
Published on: June 9, 2020
Somatic gene mutations involved in DNA damage response/Fanconi anemia signaling are tissue- and cell-type specific in
Sudhir Kumar Rai1,2, Wei Du3, Jun Zhang4
1University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, United States.
Abstract:
With significant advancements in the study of DNA Damage Response (DDR) and Fanconi Anemia (FA) signaling, we previously introduced the term "FA signaling" to encompass "all signaling transductions involving one or more FA proteins." This network has now evolved into the largest cellular defense network, integrating over 30 key players, including ATM, ATR, BLM, HRR6, RAD18, FANCA, FANCB, FANCC, BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, BRIP1, FANCL, FANCM, PALB2, RAD51C, SLX4, ERCC4, RAD51, BRCA1, UBE2T, XRCC2, MAD2L2, RFWD3, FAAP20, FAAP24, FAAP100, and CENPX. This system responds to both endogenous and exogenous cellular insults. However, the mutational signatures associated with this defense mechanism in non-FA human cancers have not been extensively explored. In this study, we report that different types of human cancers are characterized by distinct somatically mutated genes related to DDR/FA signaling, each accompanied by a unique spectrum of potential driver mutations. For example, in pan-cancer samples, ATM emerges as the most frequently mutated gene (5%) among the 31 genes analyzed, with the highest number of potential driver mutations (1714), followed by BRCA2 (4% with 970 putative driver mutations). However, this pattern is not universal across specific cancer types. For example, FANCT is the most frequently mutated gene in breast (14%) and liver (4%) cancers. In addition, the alteration frequency of DDR/FA signaling due to these mutations exceeds 70% in a subtype of prostate cancer, with each subtype of brain, breast, lung, and prostate cancers displaying distinct patterns of gene alteration frequency. Furthermore, these gene alteration patterns significantly impact patient survival and disease-free periods. Collectively, our findings not only enhance our understanding of cancer development and progression but also have significant implications for cancer patient care and prognosis, particularly in the development of effective therapeutic strategies.
Insights
Cancer mutations in DNA Damage Response (DDR) and Fanconi Anemia (FA) signaling pathways vary by cancer type. These distinct mutational signatures impact patient survival and therapeutic strategies.
Area of Science:
- Genomics and Cancer Biology
- DNA Damage Response (DDR) and Fanconi Anemia (FA) Signaling Pathways
Background:
- The DNA Damage Response (DDR) and Fanconi Anemia (FA) signaling network, involving over 30 proteins, is crucial for cellular defense against DNA damage.
- While the FA signaling network is well-studied, its specific mutational signatures in non-Fanconi Anemia human cancers remain underexplored.
Purpose of the Study:
- To investigate the distinct somatically mutated genes within the DDR/FA signaling network across various human cancer types.
- To identify unique mutational patterns and their association with potential driver mutations in different cancers.
- To explore the impact of these DDR/FA gene alterations on patient survival and disease-free periods.
Main Methods:
- Analysis of somatic mutations in 31 DDR/FA signaling genes across diverse human cancer types.
- Identification of frequently mutated genes and their associated potential driver mutations.
- Correlation analysis between gene alteration frequencies, cancer subtypes, and patient outcomes (survival, disease-free period).
Main Results:
- ATM and BRCA2 are the most frequently mutated DDR/FA genes in pan-cancer analysis, but specific mutations vary by cancer type (e.g., FANCT in breast and liver cancer).
- Distinct patterns of DDR/FA gene alteration frequencies were observed across subtypes of brain, breast, lung, and prostate cancers, with one prostate cancer subtype exceeding 70% alteration.
- DDR/FA gene alterations significantly impact patient survival and disease-free periods across different cancer types.
Conclusions:
- Human cancers exhibit unique mutational landscapes within the DDR/FA signaling network, influencing cancer development and progression.
- These findings highlight the importance of DDR/FA signaling pathway alterations in cancer prognosis.
- Understanding these specific mutational signatures can inform the development of targeted therapeutic strategies and improve patient care.
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