Jul 2026· Cancer Letters· Vol 657, pp.
218703
· 0 citations· 94 references
Medicine
TL;DR
Current evidence on disease burden, etiologic heterogeneity, age-related genomic features, and treatment-relevant tumor immune context in early-onset lung cancer are synthesized, with a focus on issues relevant to clinical interpretation and management prioritization.
Abstract
Early-onset lung cancer, commonly defined as disease diagnosed at or before 50 years of age, represents a growing but insufficiently characterized subset of lung cancer in clinical practice. However, much of the evidence informing current diagnostic and therapeutic practice has been generated from age-unselected or older, smoking-dominant populations and may not fully capture the clinical characteristics of younger patients. Consequently, younger individuals with lung cancer may face delayed risk recognition, incomplete molecular evaluation, and treatment decisions not fully informed by age-associated clinicobiological features. Accumulating evidence indicates that early-onset non-small cell lung cancer (NSCLC) is enriched for actionable oncogenic alterations, particularly gene fusions and selected HER2/ERBB2 alterations, and is frequently associated with lower tumor mutational burden and a less inflamed tumor microenvironment. Although these features do not yet establish early-onset NSCLC as a separate treatment category, they support age-informed refinement of guideline-based management, particularly in initial molecular testing, interpretation of immunotherapy-relevant immune features, treatment transitions, and survivorship planning. In this review, we synthesize current evidence on disease burden, etiologic heterogeneity, age-related genomic features, and treatment-relevant tumor immune context in early-onset lung cancer, with a focus on issues relevant to clinical interpretation and management prioritization. We further outline age-informed clinical management for molecular evaluation, resistance reassessment, and survivorship care, aiming to complement rather than replace established NSCLC guidelines for patients aged ≤50 years.
The incidence of early‐onset prostate cancer (EOPC) is rising, and by 2045 a 24.5% increase in cases and a 50% rise in mortality are projected. Accumulating evidence indicates that EOPC represents a distinct disease entity, characterized by unique molecular features, risk factor profiles, and clinical behavior that differ from standard‐onset prostate cancer (SOPC). Nevertheless, research in this field remains nascent, and no consensus exists regarding the optimal management of EOPC. We synthesize current evidence on the epidemiology, molecular pathology, clinicopathological characteristics, survival, management, and early detection of EOPC. EOPC exhibits a distinctive molecular landscape, with TMPRSS2–ERG fusions occurring in 63–90% of cases as a hallmark alteration, whereas mutations in PTEN, SPOP, and CHD1 are significantly less frequent. Notably, the prevailing focus on hereditary EOPC has inadvertently led to the neglect of sporadic cases, which dominate clinical practice. Although localized EOPC confers no significant prognostic advantage over SOPC, high‐risk or metastatic early‐onset disease substantially elevates prostate‐cancer‐specific mortality. By critically appraising the existing evidence, we identify key knowledge gaps, such as the understudied sporadic EOPC subgroup and the lack of dedicated clinical trials, and propose future research directions to inform early detection and optimize therapeutic strategies for this unique patient population.
Early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before age 50, has
become a rapidly increasing global health concern. In contrast to declining rates in older adults, EOCRC incidence has nearly doubled in several high-income countries since the early 1990s and is rising in more than half of countries worldwide, particularly among individuals born after the 1960s, reflecting a clear birth‑cohort effect. In the United States, colorectal cancer is now the leading cause of cancer-related death in men under 50 and the second leading cause in women of the same age. Although hereditary syndromes such as Lynch syndrome and familial adenomatous polyposis account for 16--20% of cases, most EOCRC is sporadic and linked to environmental exposures, lifestyle factors, gut microbiome dysbiosis, and early‑life influences.
EOCRC displays distinct molecular features compared with late-onset disease, including lower
frequencies of BRAF and KRAS mutations, higher rates of microsatellite instability-high tumors outside hereditary contexts, and enrichment of TP53 and CTNNB1 alterations. Clinically, EOCRC often
presents at advanced stages, shows rectal predominance, and is associated with diagnostic delays of up to six months due to misattribution of symptoms to benign conditions. In response to rising incidence, major U.S. guidelines now recommend initiating colorectal cancer screening at age 45. Treatment increasingly incorporates immunotherapy for mismatch repair-deficient tumors, with neoadjuvant PD‑1 blockade producing exceptional pathological complete response rates. This review summarizes current evidence on EOCRC epidemiology, biology, clinical presentation, screening, and treatment, and highlights emerging directions including liquid biopsy, artificial intelligence, and microbiome-based strategies.
A. Sohaib, Ashwaq Salami, Wesal Alghwyeen et al.· Integrated Oncology Diagnost...· 0 citations
Early-onset colorectal cancer (EOCRC), conventionally defined as colorectal cancer diagnosed before the age of 50 years, has become one of the most important and unsettling epidemiologic shifts in gastrointestinal oncology. This review critically synthesizes recent evidence on EOCRC epidemiology, risk architecture, life-course carcinogenesis, molecular and microbiome-associated mechanisms, diagnostic delay, screening limitations, treatment considerations, and survivorship needs, with the aim of reframing EOCRC as an age-attuned clinical and biological challenge rather than a simple early presentation of conventional colorectal cancer. Recent population-based analyses confirm that EOCRC incidence is increasing across multiple countries and birth cohorts, with a disproportionate contribution of distal colon and rectal cancers. These data suggest that the rise of EOCRC is unlikely to be explained by improved detection alone and instead points toward changing generational exposures. Contemporary studies have moved the field beyond hereditary predisposition as the dominant explanatory model: although germline syndromes remain essential to identify, most EOCRC is sporadic or incompletely explained by known inherited risk. Recent literature increasingly implicates metabolic dysfunction, obesity, westernized dietary patterns, early-life exposures, inflammation, antibiotic-associated microbial disruption, and host–microbiome disequilibrium. Particularly important are emerging genomic data linking colibactin-associated mutational signatures to younger-onset disease, supporting the hypothesis that microbial genotoxicity may imprint early driver events long before clinical diagnosis. In parallel, recent clinical studies show that EOCRC is frequently symptomatic, yet diagnosis is commonly delayed because alarm features such as rectal bleeding, abdominal pain, altered bowel habits, and anaemia are often underestimated in younger adults. EOCRC is best understood as a heterogeneous, life-course disease shaped by the convergence of inherited susceptibility, environmental and metabolic exposures, microbiome-mediated biology, tumour site, diagnostic-system factors, and survivorship context. Lowering the average-risk screening age to 45 years is necessary but insufficient, because many cases still occur below routine screening thresholds. A modern EOCRC strategy must therefore combine risk-adapted prevention, improved family-history capture, timely investigation of red-flag symptoms, systematic germline and tumour profiling, and treatment planning that accounts for decades of survivorship. Future progress will depend on moving beyond age alone toward integrated models that connect epidemiology, exposome biology, microbial mutagenesis, precision early detection, and age-specific care.
Magda Grześkiewicz-Szostak, K. Gęca, M. Skórzewska· Current Oncology Reports· 0 citations
Introduction The characteristics of early-onset lung cancer (EOLC) have not been extensively studied. Our research aimed to comprehensively assess the clinicopathological, genetic features and prognosis of EOLC. Materials and methods In this retrospective study of lung cancer patients diagnosed at 26 Chongqing hospitals between January 2019 and December 2022 (18-74 years), we stratified them into early-onset lung cancer (<50 years) and late-onset lung cancer (≥50 years) groups. Furthermore, we used propensity score matching to balance baseline characteristics, compare overall survival and lung cancer-specific survival between early-onset lung cancer (EOLC) and late-onset lung cancer (LOLC) groups, and perform subgroup comparisons. Results A total of 6,883 lung cancer patients were included in the final analysis, comprising 690 patients with EOLC and 6,193 patients with LOLC. Compared with the LOLC group, the EOLC group had more females and never-smokers. In clinical features, EOLC patients predominantly had adenocarcinoma (69.7% vs. 52.2%), more often presented with stage IV disease (49.3% vs. 44.0%), and had higher rates of bone (22.8% vs. 16.9%) and brain metastases (18.4% vs. 10.8%), yet were more likely to undergo surgery (31.0% vs. 22.4%). Significant differences in mutation rates were observed for HER2 (10.1% vs. 1.6%). After propensity score matching, late-onset was identified as an independent risk factor for adverse survival outcomes, the median overall survival was 42.7 months for EOLC versus 32.9 months for LOLC, with 1-, 3-, and 5-year survival rates of 78.0%, 54.4%, and 42.2% in the EOLC group, compared with 75.5%, 47.8%, and 35.4% in the LOLC group. Conclusions Despite more aggressive clinicopathological features, EOLC was associated with better survival outcomes. Moreover, distinct driver gene alteration profiles highlight the need to identify targetable alterations and implement targeted therapy in this enriched population.
Hong-Liang Liu, Bibo Li, Zhikai Yu et al.· Frontiers in Oncology· 0 citations
The findings of this cohort study suggest that the high prevalence of TERT promoter variants in older patients largely explains the association between age and worse prognosis in PTC.
V. R. Marczyk, Sophie Li, Chia-Chin Wu et al.· JAMA Otolaryngology - Head a...· 0 citations
Young-onset lung cancer is enriched for never-smoking and oncogene-driven tumors, yet its inherited genetic basis remains poorly defined. We performed germline whole-genome sequencing in 251 young-onset lung cancer cases (median age 37), which we jointly analyzed with never-smoking cases (n=196; median age 68) and cancer-free controls (n=1,883). We identified enrichments of rare deleterious coding variants across 55 cancer-related gene sets, including EGFR/ERBB2 signaling and genes implicated by prior lung cancer GWAS. Exome-wide analyses of rare coding variants affirmed TP53 as a penetrant lung cancer predisposition gene (odds ratio [OR]=36.1, p=1.02x10-7) and discovered two novel exome-wide significant tumor subtype-dependent associations: IREB2 in cases with fusion-driven tumors (p=1.39x10-6) and SMAD6 in fusion-negative tumors (p=2.05x10-6). Structural variants contributed distinct risk, with enrichment in constrained, lung-expressed genes (OR=5.79, p=5.8x10-5) and very large germline deletions being markedly enriched in cases with fusion-driven tumors. Polygenic risk scores for lung cancer were inversely correlated with rare variant burden, consistent with additive risk from rare and common variants. Collectively, these findings delineate a complex germline architecture underlying susceptibility and molecular subtype in young-onset lung cancer.
J. LoPiccolo, Ryan L. Collins, Noah Fields et al.· medRxiv· 0 citations