ASCO Conference Coverage

Younger Age at Endometrial Cancer Diagnosis Associated With Higher Rates of Germline Pathogenic Variants, Lynch Syndrome

Anthony Calabro, MA

Key Highlights

  • Early-onset endometrial cancer (< 50 years) showed the highest rates of germline pathogenic variants (gPV), biallelic loss, and Lynch syndrome (LS).
  • In multivariable models, younger age remained a strong independent predictor for LS and gPV presence.
  • High-penetrance variants were found in 50% of early-onset cases, with MSH2, MSH6, and MLH1 being the most frequent.
  • Distinct germline patterns in very early-onset (<40 years) vs. age 40–49 suggest differing tumorigenic mechanisms.

In a retrospective cohort study of 1625 patients with endometrial cancer (EC), germline alterations were most prevalent among those diagnosed before age 50, highlighting the relevance of genetic testing in this younger population. This study was presented as a poster at the American Society of Clinical Oncology 2025 annual meeting in Chicago, IL.

Additionally, germline pathogenic variants (gPVs) were identified in 16% of early-onset cases, compared with 14% and 9% in patients diagnosed between ages 50-69 and ≥ 70, respectively (P = .016). Biallelic loss and Lynch syndrome (LS) were also enriched in the younger age groups, further supporting age as a critical factor in the germline etiology of EC.

Generally considered a disease of postmenopausal women, EC is increasingly diagnosed in younger patients, prompting investigations into hereditary factors. This study aimed to characterize the age-related germline mutation landscape and assess correlations with clinical and molecular features, including the prevalence of high-penetrance genes and mismatch repair deficiency.

The study included patients treated at a single institution who underwent tumor-normal sequencing from December 2024 to June 2021. Logistic regression models assessed the association between age at diagnosis and the presence of gPV, biallelic loss, and LS. Age categories were defined as < 50 years (early-onset), 50-69 years, and ≥ 70 years (later-onset).

Researchers classified 50% of gPVs as high-penetrance, with equal proportions (50%) exhibiting biallelic loss among the patients with an early-onset diagnosis. The most frequently mutated genes in this cohort included MSH2, MSH6, and MLH1. Conversely, older patients had lower rates of high-penetrance variants (14%) and biallelic loss (22%), with more gPVs found in BRCA2, BRCA1, and PALB2.

Multivariable analysis showed that early-onset EC was independently associated with biallelic loss (OR, 3.34; 95% CI, 1.44-7.35) and LS (HR, 3.49; 95% CI, 1.63-7.01), while later-onset EC was inversely associated with both.

Notably, within the early-onset group, those diagnosed before age 40 had lower gPV (8.9%) and LS (2.2%) rates compared with patients diagnosed between ages 40-49 (19% and 8%, respectively), suggesting distinct biological mechanisms in very early-onset EC.

“Rates of gPV, biallelic loss and LS differ across age groups for EC, with higher rates of highly penetrant genes that drive tumorigenesis enriched in younger patients,” the authors concluded.

Reference:
Wang JJ, Zhou Q, Iasonos A, et al. Age-related germline landscape of endometrial cancer: Focus on early-onset cases. Presented at: 2025 American Society of Clinical Oncology (ASCO) Annual Meeting; 2025 May 30–June 3; Chicago, IL.