Pathogenic germline variants in patients with endometrial cancer of diverse ancestry

Abstract

BackgroundRacial disparities in outcomes exist in endometrial cancer (EC). The contribution of ancestry‐based variations in germline pathogenic variants (gPVs) is unknown.MethodsGermline assessment of ≥76 cancer predisposition genes was performed in patients with EC undergoing tumor‐normal Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets sequencing from January 1, 2015 through June 30, 2021. Self‐reported race/ethnicity and Ashkenazi Jewish ancestry data classified patients into groups. Genetic ancestry was inferred from Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets. Rates of gPV and genetic counseling were compared by ancestry.ResultsAmong 1625 patients with EC, 216 (13%) had gPVs; 15 had >1 gPV. Rates of gPV varied by self‐reported ancestry (Ashkenazi Jewish, 40/202 [20%]; Asian, 15/124 [12%]; Black/African American (AA), 12/171 [7.0%]; Hispanic, 15/124 [12%]; non‐Hispanic (NH) White, 129/927 [14%]; missing, 5/77 [6.5%]; p = .009], with similar findings by genetic ancestry (p < .001). We observed a lower likelihood of gPVs in patients of Black/AA (odds ratio [OR], 0.44; 95% CI, 0.22–0.81) and African (AFR) ancestry (OR, 0.42; 95% CI, 0.18–0.85) and a higher likelihood in patients of Ashkenazi Jewish genetic ancestry (OR, 1.62; 95% CI; 1.11–2.34) compared with patients of non‐Hispanic White/European ancestry, even after adjustment for age and molecular subtype. Somatic landscape influenced gPVs with lower rates of microsatellite instability‐high tumors in patients of Black/AA and AFR ancestry. Among those with newly identified gPVs (n = 114), 102 (89%) were seen for genetic counseling, with lowest rates among Black/AA (75%) and AFR patients (67%).ConclusionsIn those with EC, gPV and genetic counseling varied by ancestry, with lowest rates among Black/AA and AFR patients, potentially contributing to disparities in outcomes given implications for treatment and cancer prevention.Plain Language Summary Black women with endometrial cancer do worse than White women, and there are many reasons for this disparity. Certain genetic changes from birth (mutations) can increase the risk of cancer, and it is unknown if rates of these changes are different between different ancestry groups. Genetic mutations in 1625 diverse women with endometrial cancer were studied and the lowest rates of mutations and genetic counseling were found in Black and African ancestry women. This could affect their treatment options as well as their families and may make disparities worse.

Moving into the modern era of molecular classification for endometrial cancer

“…56 Additionally, the MMRdeficient/MSI-H molecular subtype is associated with Lynch syndrome, an inherited cancer predisposition syndrome caused by germline pathogenic variants (gPVs) in the MMR genes, and ancestry-based variations in gPV and Lynch syndrome have been observed. 57 These ancestry-based tumor molecular differences may influence the racial/ethnic disparities in EC outcomes and are important to address in clinical trial accrual and efforts to improve health equity.…”

“…On the other hand, high TMB (≥10 mut/Mb) molecular subtypes such as MMR‐deficient/MSI‐H or POLE were less common in Black as compared with White patients with EC, and less likely to have actionable alterations including high TMB/MSI, which would preclude use of breakthrough treatments such as ICB 56 . Additionally, the MMR‐deficient/MSI‐H molecular subtype is associated with Lynch syndrome, an inherited cancer predisposition syndrome caused by germline pathogenic variants (gPVs) in the MMR genes, and ancestry‐based variations in gPV and Lynch syndrome have been observed 57 . These ancestry‐based tumor molecular differences may influence the racial/ethnic disparities in EC outcomes and are important to address in clinical trial accrual and efforts to improve health equity.…”

Racial disparities and referral for genetic counseling

“…11 Although it is tempting to wonder whether non-English-speaking patients are less likely to be referred for genetic testing, 25% of patients who identified as Hispanic, 14% as Asian, and 1.2% as Black/AA selected a language other than English as their preferred language. 8 Nevertheless, in the cohort reported by Liu et al, Black/ AA patients had the lowest referral rates to clinical genetics, and patients of Asian ancestry had the highest rates. 8 Other studies have also shown that when patients are referred for counseling, race and sociodemographic factors did not affect the likelihood of making an appointment.…”

“…8 Nevertheless, in the cohort reported by Liu et al, Black/ AA patients had the lowest referral rates to clinical genetics, and patients of Asian ancestry had the highest rates. 8 Other studies have also shown that when patients are referred for counseling, race and sociodemographic factors did not affect the likelihood of making an appointment. 12 This suggests that clinician communication with the patient and referral are a crucial strategy for increasing genetic counseling and screening in minority or underserved populations.…”

“…In this issue of Cancer, Liu et al 8 assess the rates of germline pathologic variants (gPVs) in women undergoing evaluation and treatment of endometrial cancer at the Memorial Sloan Kettering Cancer Center. They correlate this information with self-reported ancestry and referral for genetic counseling.…”