Abstract
Aneuploidy is a hallmark of colorectal cancer, yet the functional consequences of recurrent chromosome gains and losses remain largely unknown. Leveraging advances in human colon organoid culture and chromosome copy number engineering, we here identify the gain of chromosome 7 as an adaptive event following APC loss-of-function mutation. Trisomy 7 confers a cell-intrinsic fitness advantage to APC-mutant colon organoids, while selective removal of the additional chromosome 7 copy from patient-derived colon cancer organoids severely impairs colorectal cancer organoid growth. By comparing transcriptomes of isogenic disomy 7 and trisomy 7 organoid lines, we found that chromosome 7 gain promotes organoid fitness through attenuation of excessive WNT-driven stemness caused by bi-allelic APC mutation. The gain of chromosome 7 thus establishes a just-right WNT signaling state. This effect of chromosome 7 gain is conserved from early adenoma-like APC-mutant organoids to advanced colorectal cancer organoids carrying additional oncogenic driver mutations. Moreover, consistent with our organoid data, gain of chromosome 7 is particularly common in tumors of colorectal cancer patients whose APC genotypes confer relatively high WNT activity. Overall, this work demonstrates that chromosome-specific aneuploidy can act as an adaptive mechanism to optimize, rather than maximize, oncogenic signaling during tumor evolution.