Digenic Inheritance of Monoallelic MUTYH and POLE Germline Variants in Adrenocortical Carcinoma: Implications for Tumorigenesis and Immunotherapy
Jonathan Lopez1,2 | Adrien Buisson1,3 | Adel Ounnas1 | Gaelle Tachon1,3 | Alain Viari1 | Florence De Fraipont1,4 | Juliette Albuisson1,5 | Marc Barritault1,6 | Pierre-Paul Bringuier1,6 | Jean-Paul Feugeas1,7 | Anne Mc Leer1,3 | Ahmed Bouras1,8
1GCS AURAGEN, Lyon, France | 2Biochemistry and Molecular Biology Department, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre-Bénite,
France | 3Department of Biopathology, Centre Léon Bérard, Lyon, France | 4Medical Unit of Molecular Genetics, Grenoble University Hospital, Grenoble, France | 5Department of Pathology and Tumor Biology, Georges-François Leclerc Center, Dijon, France | 6Department of Pathology, Groupe Hospitalier Est, Hospices Civils de Lyon, Bron, France | 7Laboratoire de Biochimie Hôpital Jean Minjoz, Université de Franche-comté, Besançon, France | 8Laboratory of Constitutional Genetics for Frequent Cancer HCL-CLB, Centre Léon Bérard, Lyon, France
Correspondence: Ahmed Bouras (ahmed.bouras@lyon.unicancer.fr)
Received: 16 January 2025 | Revised: 26 January 2025 | Accepted: 27 January 2025
Keywords: adrenocortical carcinoma | digenic inheritance | immunotherapy | MUTYH | POLE
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 stan- dard chemotherapies and limited efficacy of immunotherapy in clinical trials.
Germline monoallelic pathogenic variants in POLE cause poly- merase proofreading-associated polyposis by impairing the proofreading function of DNA polymerase & during the DNA repair. Recent studies suggest that POLE variants may act as ge- netic 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 discontinua- tion 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 pa- tient 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 heterozygos- ity (LOH). The COSMIC MUTYH-specific mutational signa- ture, SBS36, accounted for 93% of somatic SNVs (Figure 1D). Tumor RNA sequencing further showed that MUTYH expres- sion 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
A
B
MUTYH c.536A>G p.(Tyr179Cys)
POLE c.902A>G p.(Asp301Gly)
I
45.332,800 bp
45.332.810 bp
132.876,540 bp
132.678,550
132.676.500 bp
1
COAGAATA
QCCCABOCCAGCC
GOTOCTOACCTOGCCA -COATCATOTAGG
2
BC (69)
wgs tumour
231
wqs tumour
9
P
Tumor
C
II
1
2
3
67
wqs germline
42
wgs germline
2
0
Bilateral BC (42+51)
Bilateral BC (40+50) ACC (65)
Germline
C
0
0
0
0
0
Gencode V:17
[Gencode v/32]
MUTYH
POLE
C
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19202122
x
Y
6
Absolute copy number
5
I
4
3
2
1
0
H
CELL.FRAC AMPLIF
LOH
DEL. HOMO.
Cell fraction
0.0
0.2
0.4
0.6
0.8
1.0
D
C>A
C>G
C>T
T>A
T>C
T>G
6000
4000
2000
0
25
2
2
AXA
5
5
E
K
5
MA
AXA
ARC
2
A
G
AXA
Ax
*
2
x
S
5
AXA
A
G
C>A
C>G
C>T
T>A
T>C
T>G
0.09
0.06
0.03
0.00
1
AXA
S
U
A
AXA
AXA
GxC
AXA
AxĞ
CXC
AXA
4
A
L
G
CX
G
4
G
A
C
1
E
MUTYH gene expression (N=1316) [top_rank=1290/1316=99%]
+
N
0
log2(tpm)
-2
Patient
+
the constitutional origin and the heterozygous state of the MUTYH c.536A>G p.(Tyr179Cys) variant. Additionally, a ger- mline 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].
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 investi- gation into digenic inheritance and its implications for cancer susceptibility and therapeutic response.
Acknowledgments
This research was made possible through access to the France Genomic Medicine Plan 2025 data and the AURAGEN platform.
Conflicts of Interest
The authors declare no conflicts of interest.
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.
Peer Review
The peer review history for this article is available at https://www.webof science.com/api/gateway/wos/peer-review/10.1111/cge.14721.
References
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2. L .- S. Landwehr, J. Schreiner, S. Appenzeller, et al., “A Novel Patient- Derived Cell Line of Adrenocortical Carcinoma Shows a Pathogenic Role of Germline MUTYH Mutation and High Tumour Mutational Burden,” European Journal of Endocrinology 184 (2021): 823-835, https://doi.org/10.1530/EJE-20-1423.
3. O. Michaeli, H. Ladany, A. Erez, et al., “Di-Genic Inheritance of Germline POLE and PMS2 Pathogenic Variants Causes a Unique Condition Associated With Pediatric Cancer Predisposition,” Clinical Genetics 101 (2022): 442-447, https://doi.org/10.1111/cge.14106.
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Checkpoint Inhibitors,” npj Precision Oncology 6 (2022): 15, https://doi. org/10.1038/s41698-022-00258-8.
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