Association of clonal hematopoiesis and mosaic chromosomal alterations with solid malignancy incidence and mortality

Background: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways. Methods: The authors analyzed whole genome sequencing data from the Trans-Omics for Precision Medicine Women’s Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers. Results: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03–1.64; p =.02) but not colorectal (p =.77) or lung cancer (p =.32). CHIP carriers who developed colorectal cancer also had a greater risk for advanced-stage (p =.01), but this was not seen in breast or lung cancer. CHIP was associated with increased colorectal cancer mortality both with (HR, 3.99; 95% CI, 2.41–6.62; p <.001) and without adjustment (HR, 2.50; 95% CI, 1.32–4.72; p =.004) for advanced-stage and a borderline higher breast cancer mortality (HR, 1.53; 95% CI, 0.98–2.41; p =.06). Conversely, mCA (cell fraction [CF] >3%) did not correlate with cancer risk. With higher CFs (mCA >5%), autosomal mCA was associated with increased breast cancer risk (HR, 1.39; 95% CI, 1.06–1.83; p =.01). There was no association of mCA (>3%) with breast, colorectal, or lung mortality except higher colon cancer mortality (HR, 2.19; 95% CI, 1.11–4.3; p =.02) with mCA >5%. Conclusions: CHIP and mCA (CF >5%) were associated with higher breast cancer risk and colorectal cancer mortality individually. These data could inform on novel pathways that impact cancer risk and lead to better risk stratification.