Open AccessImpact of Patient Age on Molecular Alterations of Left‐Sided Colorectal Tumors
Author(s) -
Puccini Alberto,
Lenz HeinzJosef,
Marshall John L.,
Arguello David,
Raghavan Derek,
Korn W. Michael,
Weinberg Benjamin A.,
Poorman Kelsey,
Heeke Arielle L.,
Philip Philip A.,
Shields Anthony F.,
Goldberg Richard M.,
Salem Mohamed E.
Publication year - 2019
Publication title -
the oncologist
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.176
H-Index - 164
eISSN - 1549-490X
pISSN - 1083-7159
DOI - 10.1634/theoncologist.2018-0117
Subject(s) - microsatellite instability , medicine , msh6 , colorectal cancer , mlh1 , lynch syndrome , msh2 , incidence (geometry) , oncology , gastroenterology , rectum , chromosome instability , cancer , dna mismatch repair , microsatellite , gene , genetics , allele , physics , biology , optics , chromosome
Background The incidence of colorectal cancer (CRC) in younger patients is rising, mostly due to tumors in the descending colon and rectum. Therefore, we aimed to explore the molecular differences of left‐sided CRC between younger (≤45 years) and older patients (≥65). Subjects, Materials, and Methods In total, 1,126 CRC tumor samples from the splenic flexure to (and including) the rectum were examined by next‐generation sequencing (NGS), immunohistochemistry, and in situ hybridization. Microsatellite instability (MSI) and tumor mutational burden (TMB) were assessed by NGS. Results Younger patients ( n = 350), when compared with older patients ( n = 776), showed higher mutation rates in genes associated with cancer‐predisposing syndromes (e.g., Lynch syndrome), such as MSH6 (4.8% vs. 1.2%, p = .005), MSH2 (2.7% vs. 0.0%, p = .004), POLE (1.6% vs. 0.0%, p = .008), NF1 (5.9% vs. 0.5%, p < .001), SMAD4 (14.3% vs. 8.3%, p = .024), and BRCA2 (3.7% vs. 0.5%, p = .002). Genes involved in histone modification were also significantly more mutated: KDM5C (1.9% vs. 0%, p = .036), KMT2A (1.1% vs. 0%, p = .033), KMT2C (1.6% vs. 0%, p = .031), KMT2D (3.8% vs. 0.7%, p = .005), and SETD2 (3.2% vs. 0.9%, p = .039). Finally, TMB‐high (9.7% vs. 2.8%, p < .001) and MSI‐high (MSI‐H; 8.1% vs. 1.9%, p = .009) were more frequent in younger patients. Conclusion Our findings highlight the importance of genetic counseling and screening in younger CRC patients. MSI‐H and TMB‐high tumors could benefit from immune‐checkpoint inhibitors, now approved for the treatment of MSI‐H/deficient mismatch repair metastatic CRC patients. Finally, histone modifiers could serve as a new promising therapeutic target. With confirmatory studies, these results may influence our approach to younger adults with CRC. Implications for Practice The increasing rate of colorectal cancers (CRC), primarily distal tumors, among young adults poses a global health issue. This study investigates the molecular differences between younger (≤45 years old) and older (≥65) adults with left‐sided CRCs. Younger patients more frequently harbor mutations in genes associated with cancer‐predisposing syndromes. Higher rates of microsatellite instability‐high and tumor mutational burden‐high tumors occur in younger patients, who could benefit from immune‐checkpoint inhibitors. Finally, histone modifiers are more frequently mutated in younger patients and could serve as a new promising therapeutic target. This study provides new insights into mutations that may guide development of novel tailored therapy in younger CRC patients.