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ORIGINAL RESEARCH article

Front. Med.
Sec. Pathology
Volume 11 - 2024 | doi: 10.3389/fmed.2024.1462810
This article is part of the Research Topic Crosstalk From DNA Damage to Microenvironment Changes in Carcinogenesis View all articles

Somatic Gene Mutations Involved in DNA Damage Response / Fanconi Anemia Signaling are Tissue and Cell-Type Specific among Human Solid Tumors

Provisionally accepted
SUDHIR RAI SUDHIR RAI 1Wei Du Wei Du 2Jun Zhang Jun Zhang 3Herbert Yu Herbert Yu 1Youping Deng Youping Deng 1*Peiwen Fei Peiwen Fei 1*
  • 1 University of Hawaii at Manoa, Honolulu, Hawaii, United States
  • 2 University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • 3 Breast Clinic, Mayo Clinic, Phoenix, Arizona, United States

The final, formatted version of the article will be published soon.

    With the rigorous progress achieved in DNA Damage Response (DDR) / Fanconi Anemia (FA) Signaling, we previously proposed “FA signaling”, meaning “all signaling transductions involving one or more FA proteins”. This signaling now becomes a largest cellular defense network integrated with at least 30+ players (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) in response to both endogenous and exogenous cellular insults. However, it is underperformed as to the mutational signatures associated with this defense system among human cancers without FA. Here, we report each type of human cancer tops with a different somatically mutated gene related to DDR/FA signaling in general, accompanying a different spectrum of the potential driver mutations. Such as, among pan cancer samples, ATM is the highest mutated gene (5%) among 31 genes queried, also featuring the highest potential driver mutations (1714) followed by BRCA2 (4% with 970 putative driver mutations). However, this is not a universal pattern for a specific type of human cancer, such as, the highest mutated gene is FANCT (14%) in breast cancer and liver cancer (4%). In addition, the altered frequency of the DDR/FA signaling resulting from these mutations was as high as >70% in a subtype prostate cancer, and each subtype of human cancer studied among brain, breast, lung and prostate is topped with a distinct gene altered frequency. Furthermore, those patterns of gene alterations significantly impact patient’s survival time and disease-free period. Collectively, these findings will not only enhance our understanding of cancer development and progression but also influence cancer patient care and prognosis, in terms of establishing effective, therapeutic strategies.

    Keywords: DNA damage response (DDR), Fanconi Anemia (FA) Signaling, genome instability, DNA interstrand cross-links, Somatic mutation ATR, BLM, HRR6, RAD18

    Received: 10 Jul 2024; Accepted: 28 Aug 2024.

    Copyright: © 2024 RAI, Du, Zhang, Yu, Deng and Fei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Youping Deng, University of Hawaii at Manoa, Honolulu, 96822, Hawaii, United States
    Peiwen Fei, University of Hawaii at Manoa, Honolulu, 96822, Hawaii, United States

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