Digenic Inheritance of Monoallelic MUTYH and POLE Germline Variants in Adrenocortical Carcinoma: Implications for Tumorigenesis and Immunotherapy

Abstract

Collision of monoallelic MUTYH and POLE germline variants in a patient with adrenocortical carcinoma who achieved a strong response to immunotherapy.

1.

Biallelic germline inactivation of MUTYH, a base excision repair gene, increases colorectal cancer risk. The impact of monoallelic MUTYH mutations is less clear, though recent studies suggest a role in certain tumors, including adrenocortical carcinoma (ACC) [1, 2], a cancer characterized by poor response to standard chemotherapies and limited efficacy of immunotherapy in clinical trials.

Germline monoallelic pathogenic variants in POLE cause polymerase proofreading‐associated polyposis by impairing the proofreading function of DNA polymerase ε during the DNA repair. Recent studies suggest that POLE variants may act as genetic modifiers of clinical severity in other cancer‐predisposing syndromes through a synergistic effect with other cancer‐related genes [3, 4].

This report presents a patient with ACC who carried germline monoallelic variants in both MUTYH and POLE. Diagnosed at 65 with high‐grade ACC, the tumor displayed a Weiss score of 9, a Ki‐67 > 50%, and capsular rupture, all indicative of poor prognosis. Despite an initial plan for adjuvant chemotherapy with carboplatin and etoposide, the introduction of mitotane caused significant hepatic cytolysis, leading to discontinuation of the treatment after just two cycles. Declining further chemotherapy, the patient was placed under surveillance with regular imaging and endocrine follow‐up. Pulmonary metastasis subsequently developed, leading to her inclusion in the ‘France Génomique Plan 2025’ (https://pfmg2025.fr/) for tumor and germline whole genome sequencing (WGS) to better characterize the genetic drivers of her disease. Written informed consent was obtained from the patient in compliance with French law governing diagnostic genetic testing. The patient pedigree is presented in Figure 1A. Tumor WGS revealed microsatellite instability (MSI = 26%; threshold > 20%), high tumor mutation burden (TMB = 12.3 Mut/Mb; threshold > 10 Mut/Mb), and a significantly rearranged chromosomal profile with 52% genome alteration (Figure 1C). Biallelic MUTYH inactivation was detected, involving a pathogenic missense variant: c.536A>G p.(Tyr179Cys) with loss of heterozygosity (LOH). The COSMIC MUTYH‐specific mutational signature, SBS36, accounted for 93% of somatic SNVs (Figure 1D). Tumor RNA sequencing further showed that MUTYH expression was in the lowest 1% compared to 1316 tumors analyzed using the AURAGEN platform (Figure 1E). Tumor analysis also revealed pathogenic variants in TP53 (c.560‐1G>T; p.?; VAF:91%), ATRX (c.4063G>T; p.(Glu1355*); VAF:60%) and APC (c.4660G>T; p.(Glu1554)*; VAF 53%). These variants were absent at the germline level. Germline WGS asserted the constitutional origin and the heterozygous state of the MUTYH c.536A>G p.(Tyr179Cys) variant. Additionally, a germline heterozygous POLE (NM_006231.3) variant, c.902A>G p.(Asp301Gly), was identified (Figure 1B). This rare variant, located in the exonuclease domain, has a gnomAD European non‐Finnish population frequency of 1.759e‐05, a high CADD‐phred score of 29.4, and intermediate functional impact based on CRISPR‐Cas9 assays [5].

FIGURE 1.

(A) Family pedigree indicating the proband (black arrow). BC: breast cancer; ACC: adrenocortical carcinoma. (B) IGV browser visualization of germline and somatic WGS showing MUTYH and POLE variants with loss of heterozygosity for MUTYH. (C) Tumor chromosomal profile showing copy number alterations. (D) Spectrum of somatic point mutations (SNVs) highlighting SBS36 dominance. (E) Boxplot showing MUTYH underexpression in the patient's tumor compared to 1316 other tumors, falling within the lowest 1%.

Based on the MSI profile and the high TMB, the patient was treated with Durvalumab and Tremelimumab, achieving near‐complete remission after 21 months.

This case illustrates a digenic condition with MUTYH and POLE germline variants in a patient with ACC who achieved a strong response to immunotherapy. The MUTYH‐specific mutational signature and somatic LOH strongly support MUTYH as the primary tumor driver. Although no POLE‐associated somatic mutational signature was identified, this case aligns with other studies [1, 2] suggesting that monoallelic MUTYH variants may predispose to ACC and highlights the need for further investigation into digenic inheritance and its implications for cancer susceptibility and therapeutic response.

Conflicts of Interest

The authors declare no conflicts of interest.

Peer Review

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer‐review/10.1111/cge.14721.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.