Kim IH, et al. J Gastric Cancer. 2025 Jan;25:e11. https://doi.org/10.5230/jgc.2025.25.e11

The fundamental principle of precision oncology is centralized on the identification of therapeutically exploitable targets that provides individual patients with cancer an opportunity to make informed decisions on a personalized level. To facilitate and adopt such concepts within clinical practice, we have initiated a nationwide, multi-institutional precision oncology screening program to examine and enroll patients into the most appropriate clinical trial based on their tumor's unique molecular properties. To determine the prevalence of essential major driver mutations and to explore their dynamic associations at both molecular and pathway levels, we present a comprehensive overview on the genomic properties of East Asian patients with cancer. We further delineate the extent of genomic diversity as well as clinical actionability in patients from Western and Eastern cultures at the pan-cancer and single-tumor entity levels. To support fellow oncology communities in future investigations involving large-scale analysis, all data have been made accessible to the public (https://kmportal.or.kr). Significance: We present a comprehensive overview of molecular properties of East Asian pan-cancer patients and demonstrate significant diversity in terms of genomic characteristics as well as clinical utility compared with patients with European ancestry. The results of this study will lay the groundwork for designing personalized treatments in the clinical setting. See related commentary by Moyers and Subbiah, p. 886. This article is highlighted in the In This Issue feature, p. 873

PURPOSE: The spectrum of somatic mutations among women with endometrial cancer (EC) younger than 50 years (early-onset EC) remains unknown. We investigated distinct somatic mutation patterns among early-onset and late-onset (age ≥ 50 years) EC patients.METHODS: This cohort study included individuals age 18+ years diagnosed with pathologically confirmed EC in the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE, v9.1) consortium. We explored tumor mutational burden (TMB) and genomic patterns of EC by age at clinical sequencing using multivariable regression models adjusted for race, ethnicity, histology, sequencing assay, sample type, and TMB.RESULTS: Among 2,425 women with EC, 176 (7.3%) had early-onset EC and 1,923 (79.3%) had nonhypermutated (< 17.78 mutations/Mb) tumors. TMB significantly differed across age and histology groups. Among nonhypermutated ECs, early-onset patients had significantly lower odds of presenting with nonsilent FGFR2 and PIK3R1 somatic mutations compared with late-onset EC patients in adjusted models ( FGFR2: odds ratio [OR] = 0.18, 95% CI, 0.04 to 0.76; PIK3R1: OR = 0.54, 95% CI, 0.31 to 0.92). By contrast, early-onset EC patients had increased odds of presenting with nonsilent CTNNB1 and BRCA2 mutations compared with late-onset patients ( CTNNB1: OR = 3.32, 95% CI, 2.14 to 5.16; BRCA2: OR = 4.01, 95% CI, 1.55 to 10.38). Subsequent analyses stratified by race, ethnicity, and tumor histology identified distinct patterns of APC, KMT2D, KMT2C, and KRAS by race, ethnicity, and PTEN and APC patterns by histologic subtypes.CONCLUSION: Early-onset EC harbors a unique genomic landscape compared with late-onset disease. A distinct molecular phenotype of early-onset EC provides novel insights into a unique etiology and may yield clinical implications for developing targeted treatment modalities for younger patients.

Background: Microsatellite instability (MSI) and tumor mutational burden (TMB) are predictive biomarkers for pan-cancer immunotherapy. The interrelationship between MSI-high (MSI-H) and TMB-high (TMB-H) in human cancers and their predictive value for immunotherapy in lung cancer remain unclear. Methods: We analyzed somatic mutation data from the Genomics Evidence Neoplasia Information Exchange (n = 46,320) to determine the relationship between MSI-H and TMB-H in human cancers using adjusted multivariate regression models. Patient survival was examined using the Cox proportional hazards model. The association between MSI and genetic mutations was assessed. Results: Patients (31–89%) with MSI-H had TMB-low phenotypes across 22 cancer types. Colorectal and stomach cancers showed the strongest association between TMB and MSI. TMB-H patients with lung cancer who received immunotherapy exhibited significantly higher overall survival [HR, 0.61; 95% confidence interval (CI), 0.44–0.86] and progression-free survival (HR, 0.65; 95% CI, 0.47–0.91) compared to the TMB-low group; no significant benefit was observed in the MSI-H group. Patients with TMB and MSI phenotypes showed further improvement in overall survival and PFS. We identified several mutated genes associated with MSI-H phenotypes, including known mismatch repair genes and novel mutated genes, such as ARID1A and ARID1B. Conclusions: Our results demonstrate that TMB-H and/or a combination of MSI-H can serve as biomarkers for immunotherapies in lung cancer. Impact: These findings suggest that distinct or combined biomarkers should be considered for immunotherapy in human cancers because notable discrepancies exist between MSI-H and TMB-H across different cancer types.

It is largely unknown whether genetic susceptibility contributes to tumor immune infiltration in common cancers. We systematically investigated the association between polygenic risk scores (PRSs) and tumor immune infiltration in common cancers. First, we constructed a PRS for common cancers using the risk variants identified in previous genome-wide association studies. Then, we analyzed 139 immune traits predicted by previous studies by examining gene expression data in tumor tissues from The Cancer Genome Atlas (TCGA). We applied regression analyses to evaluate the associations between PRS and immune traits for each cancer overall and stratified by stage, including 2160 pathologically confirmed cases of breast, colorectal, lung, ovarian, pancreatic, and prostate cancers in the White population. At a nominal (p < 0.05) significance level, we identified 31 significant associations between PRS and immune traits. In the analyses stratified by stage for breast, colorectal, lung adenocarcinoma, and lung squamous cell carcinoma, we identified 65 significant associations, including 56 associations that were undetected by the overall analysis. This study provides evidence for genetic risk factors affecting immune infiltration and provides novel insights into the role of genetic susceptibility in immune responses, underlying cancer development, prognosis, and the potential role of an early diagnostic or therapeutic targeting strategy.

Background: We aimed to investigate racial/ethnic, age of onset, and sex disparities in tumor genomic profiles across 34 solid cancer types. Methods: We analyzed tumor genomic and clinical data from 104,399 patients with 34 solid cancer types from the Genomics Evidence Neoplasia Information Exchange consortium (2011–2023). Patients were classified by race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, Asian or Pacific Islander, and other/unknown), age at onset (<50, 50–69, ≥70 years), and sex. We assessed the prevalence and spectrum of somatic mutations and compared tumor mutational burden (TMB) across groups using adjusted regression models. Results: Significant racial/ethnic and age of onset differences in TMB were observed in 15 and 21 cancer types, respectively. Males had higher TMB in non–small cell lung cancer, melanoma, hepatobiliary cancer, nonmelanoma skin cancer, and germ cell cancers, whereas females had higher TMB in colorectal, glioma, and head and neck cancers. Notable racial/ethnic disparities were found in frequently mutated genes. Compared with non-Hispanic White patients, Asian or Pacific Islander [OR = 0.23 (95% confidence interval, 0.19–0.29)] and Hispanic [0.56 (0.44–0.71)] patients had lower frequencies of KRAS mutations in non–small cell lung cancer, whereas non-Hispanic Black patients had higher frequencies of KRAS in colorectal cancer [1.61 (1.37–1.90)], TP53 in breast cancer [1.77 (1.51–2.07)], and endometrial cancer [2.28 (1.66–3.12)]. Older patients generally had more mutated genes although some genes in seven cancer types showed higher frequencies in patients below 50. Conclusions: Distinct spectrums of somatic mutations exist across various racial/ethnic, age of onset, and sex groups. Impact: This study presents a pan-cancer assessment of disparities in tumor genomic profiles and can enhance our understanding of disparities in cancer etiology and prognosis.