AUTHOR=Rai Sudhir Kumar , Du Wei , Zhang Jun , Yu Herbert , Deng Youping , Fei Peiwen 

TITLE=Somatic gene mutations involved in DNA damage response/Fanconi anemia signaling are tissue- and cell-type specific in human solid tumors

JOURNAL=Frontiers in Medicine

VOLUME=Volume 11 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1462810

DOI=10.3389/fmed.2024.1462810

ISSN=2296-858X

ABSTRACT=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.