期刊
NATURE MEDICINE
卷 28, 期 8, 页码 1646-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41591-022-01930-z
关键词
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资金
- National Cancer Institute (NCI) Cancer Center Support Grant (CCSG) [P30 CA008748-53]
- NCI Cancer Center Support Grant (CCSG) [P30 CA08748]
- National Institutes of Health (NIH) [T32 GM132083]
- NIH/NCI early career development award [K08 CA255574]
- NIH/NCI [R37 248289]
The incidence of rectal cancer is increasing in younger patients. Neoadjuvant therapy can avoid surgery, but determining response-related factors is important. APC mutations are associated with aggressive behavior, KRAS mutations with increased risk of relapse, and overexpression of IGF2 and L1CAM with decreased treatment response. In addition, RNA-sequencing can identify immune hot tumors with better response to neoadjuvant therapy. DNA and RNA sequencing can serve as biomarkers for treatment response in rectal cancer patients, informing non-operative treatment strategies.
The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival. DNA and RNA sequencing in large cohorts of patients with rectal cancer treated with neoadjuvant therapies identifies biomarkers of response that could inform patient selection for non-operative treatment strategies.
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