This review summarizes experimental, cytogenetic, and sequencing evidence to support the following arguments: (1) loss of function (LOF) of the EWSR1 gene may promote chromosomal instability (CIN); (2) CIN is the mechanistic basis for the LOH or CNAs in entire chromosomes or chromosomal segments; (3) gain of function of chimeric EWSR1-ETS proteins promote replication stress (RS) and probably foster CIN; and (4) recurrent secondary lesions (e.g., STAG2, CDKN2A and TP53) emerge within the CIN-permissive context. The gene discussed is TP53; the disease is cervical squamous intraepithelial neoplasia.