AbstractGenetic variations among individuals within a population, or host genetics, determine disease susceptibility or resistance. Here we show that heterozygosity ofhsrω, a gene coding for a long noncoding architectural RNA (arcRNA), displays cancer susceptibility inDrosophila.Imaginal epithelia mutant for a null allele ofhsrω, hsrω66exhibits chronic stress, marked by loss of growth and proteostasis, besides cell death. Imaginal epithelia of larvae heterozygous forhsrω66also show cellular stress, but conditionally: for instance, upon heat shock. Somatic clones displaying loss of Lgl tumor suppressor in such stress-sensitive imaginal epithelia ofhsrω66heterozygotes develop into metastatic tumors, unlike those induced in wild type epithelia wherein these are eliminated by intrinsic tumor suppression. Further, cell-autonomous gain or loss ofhsrωinlglmutant clones, too, results in their tumor progression. Finally, we note a transcriptional increase in human sat III arcRNA, a functional analog ofDrosophila hsrω,in cancer cell lines. Loss of sat III decreases the viability of cancer cells under stress. Our findings suggest pervasive roles of arcRNA-coding genes as host genetic modifiers of cancer via their regulation of cell homeostasis.Summary statementHeterozygosity forhsrω,a gene coding for a long noncoding architectural RNA inDrosophila,induces hypersensitivity to physiological stress and promotes cancer progression in oncogenically targeted cells.