Increased Risk of Acute Myelogenous Leukemia After Early Onset but Not Late-Onset Colorectal Cancer

Background: Early onset colorectal cancer in persons younger than 50 years is increasingly common. Clinical and molecular characterizations reveal a distinctive disease. Thirty percent of patients have mutations of hereditary cancer syndromes, especially Lynch syndrome. A recent analysis, testing germline DNA for mutations in 25 cancer susceptibility genes, showed that some patients younger than 50 years had mutations of high-penetrance colorectal cancer genes such as APC (adenopolyposis coli). Others had mutations in high-penetrance or moderate-penetrance genes not traditionally associated with colorectal cancer, such as ATM (ataxia telangiectasia mutated), whereas still others had low penetrance colorectal cancer genes. In the current study, we examined the incidence of second cancers following early onset (age less than 50 y) colorectal cancer. Methods: The initial study population was assembled using records from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The SEER*Stat MP-SIR (multiple primary-standardized incidence ratio) tool was used to calculate SIRs and excess risk for second primary malignancies. The SIR is expressed as the ratio of observed-to-expected (O/E) cases. We used The Cancer Genome Atlas (TCGA) and AACR Project Genie for genetic analysis. The data were accessed with the online Xena Browser and cBioportal. Results: Acute myelogenous leukemia (AML) O/E ratios were significantly >1 in patients aged less than 50 years, at 12 to 59 months after colorectal cancer. In patients aged 50 years and older, O/E ratios were equal to 1 or quite close at 12 to 59 months after colorectal cancer. Alterations in 3 AML genes, CEBPA-AS1, MLLT1, and MLLT6, affected the prognosis of colorectal cancer patients less than 50 years but not older than 50 years. One AML gene, FLT3, had the highest copy number alteration frequency of any gene in 1438 colorectal patients 18 to 48 years of age. Genetic alterations of FLT3/TP53 were mutually exclusive. Genetic alterations of FLT3/JAK2 and JAK2/CTNNB1 were co-occurrent. Conclusion: These observations suggest that early onset colorectal cancer and AML may be related diseases.