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Cancer Genetics
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Cancer Genetics
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Case Report
A novel lynch syndrome kindred with hereditary adrenal cortical carcinoma
Kripa Ahuja a,*, Ranjit Goudar a,b
a Eastern Virginia Medical School, Norfolk, VA, USA
b Virginia Oncology Associates, Norfolk, VA, USA
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ARTICLE INFO
Keywords:
Lynch syndrome Muir-Torre syndrome Adrenal cortical carcinoma Cancer screening Somatic tumor testing
ABSTRACT
Background: Adrenal cortical carcinoma (ACC) is an extremely rare malignancy, and advanced ACC carries a very poor prognosis. Early detection is critical since early-stage disease can be cured with surgical resection. ACC can be seen in Lynch syndrome; this case and review of the literature provide insight as to the potential biological origin of this malignancy. Clinicians should be aware of this association and the potential impact on cancer screening in these kindreds.
Case Presentation: We describe a novel kindred with hereditary adrenal cortical carcinoma and the Muir- Torre syndrome, a phenotypic variant of Lynch syndrome that includes sebaceous neoplasms and visceral malig- nancies. We report a 59-year-old Caucasian man with an MSH2 deletion who was diagnosed with metastatic adrenal cortical carcinoma. The patient’s brother also had a history of adrenal cortical carcinoma. The patient’s cancer initially responded to immunotherapy with pembrolizumab. Somatic genetic testing performed on a tumor biopsy did not identify the germline MSH2 deletion.
Conclusions: A review of the literature identifies an association between germline MSH2 mutations and ACC, suggesting a potential biological basis for carcinogenesis. This case highlights the importance of ACC screening for patients with Lynch Syndrome and a family history of adrenal cortical carcinoma due to the high mortality from this malignancy. This case also highlights the importance of separate germline and somatic testing for patients with a concerning personal or family history of cancers.
Background
Lynch syndrome (LS) is one of the most common hereditary cancer syndromes, with a prevalence of 1 in every 279 people in the United States [1]. Lynch syndrome is caused by germline mutations in mismatch repair genes (MMR), including MSH2, MLH1, MSH6, PMS2, or EPCAM [1]. Mutations in these genes create microsatellite instability which alters the expression of tumor suppressor genes and can result in higher rates of colorectal, endometrial, and genitourinary malignancy [1]. Muir-Torre Syndrome (MTS) is considered a phenotypic subtype of Lynch syndrome [2]. 90 % of patients with MTS have an underlying mutation in the MSH2 gene [2], including our patient.
Adrenal cortical carcinoma (ACC) is a very rare and aggressive ma- lignancy [3]. Germline genetic testing, including for TP53 and mismatch repair genes, is recommended for all patients with ACC [4].
The prevalence of LS among patients with adrenal cortical carcinoma is 3.2 % [3]. ACC is not mentioned in the current NCCN guidelines for
genetic assessment of patients with colorectal cancer and ACC screening is not currently recommended for patients with LS [5]. The role of the mismatch repair genes and microsatellite instability in adrenal tumori- genesis remains unclear [3].
Early-stage ACC is treated with surgical resection but carries a high risk of recurrence and mortality [6]. Standard treatment options for advanced ACC include mitotane to block adrenal hormone production and cytotoxic chemotherapy [7]. Identifying patients with ACC and underlying Lynch syndrome can lead to additional therapeutic options for these patients [7]. Immunotherapy with the PD-1 inhibitors pem- brolizumab, nivolumab, and dostarlimab has been approved for the treatment of advanced mismatch-repair deficient solid tumors [7]. Pembrolizumab has shown activity as second-line therapy for ACC, though some of those patients who responded did have underlying Lynch syndrome [7].
Next-generation sequencing (NGS) on tumor samples detects somatic mutations using a selected set of cancer-associated genes, and if
* Corresponding author.
E-mail address: ahujak@evms.edu (K. Ahuja).
https://doi.org/10.1016/j.cancergen.2024.11.005
deficient mismatch repair proteins or a pattern of microsatellite insta- bility are detected, patients with any type of advanced cancer could be eligible for immunotherapy [8]. The variant allele fraction (VAF) may be used to infer whether a variant comes from somatic cells or is an inherited variant when a matched sample of germline DNA is not pro- vided [9]. If tumor testing shows a pathogenic variant present at a variant allele fraction (VAF) of approximately 50 %, that raises concern about a potential underlying germline mutation [8]. However, somatic tumor testing has a low sensitivity for the detection of germline muta- tions [8] and is not an appropriate screening test or a substitute for germline testing.
Case presentation
A White male patient had a colonoscopy at age 49 showing a 2 cm sigmoid colon polyp containing intramucosal adenocarcinoma. A review of the family history determined that the patient’s brother passed away from adrenal cortical carcinoma in his 40 s, while the patient’s mother passed away from metastatic colon cancer at 46. The patient was sub- sequently found to have a sebaceous adenoma on the abdomen at 50. This skin finding raised concern for Muir-Torre syndrome [2], and he was referred for genetic testing that showed a pathogenic MSH2 deletion in exon 5, confirming the MTS variant of Lynch syndrome [2]. The pa- tient then developed a sebaceous carcinoma on the right ear at 55. He had a second sebaceous carcinoma on the abdomen at 56.
At 59, the patient presented with symptoms of abdominal pain and marked fatigue. Examination showed lower extremity edema. Imaging showed an extremely large 16.7 cm mass in the right adrenal gland (Fig. 1.), extending through the right adrenal vein into the inferior vena
cava and terminating immediately below the right atrium. Liver lesions were present, concerning for metastases.
A biopsy of a liver lesion confirmed metastatic ACC. Due to the un- derlying MSH2 mutation, he was initially treated with the PD-1 antibody pembrolizumab and experienced symptomatic relief of abdominal pain and fatigue. CT scan showed stable disease after 9 weeks of pem- brolizumab. Restaging CT after 16 weeks showed significant progression in one of the liver metastases. Pembrolizumab was continued, and standard multiagent chemotherapy with etoposide, doxorubicin cisplatin (EDP), and mitotane were added.
Next-generation sequencing was performed on the liver biopsy to search for actionable mutations. Importantly, this testing did not iden- tify the underlying germline MSH2 deletion. Microsatellite instability testing was attempted but was unsuccessful per the performing lab.
Discussion
Clinical cancer genetics is based on the careful description and evaluation of rare individuals and families. Published guidelines serve as a starting point to direct screening, but clinicians must personalize guideline-based screening based on the gene of interest and family his- tory, including the type and age of onset of associated cancers. This novel case describes a hereditary ACC kindred in a Lynch syndrome family, which can have implications for cancer screening.
Though not mentioned in the NCCN guidelines [5], adrenal cortical carcinoma is associated with Lynch syndrome [3]. A comprehensive literature review was conducted and shows several reported cases of ACC in patients with confirmed germline mutations in mismatch repair genes (Table 1). We describe a novel Lynch syndrome kindred with two
0
R
| Sex | Age at diagnosis of ACC | Gene | Mutation | Lynch- associated cancer | Reference |
|---|---|---|---|---|---|
| M | 59 | MSH2 | Del exon 5 | Colon cancer at 49 | |
| Sebaceous | |||||
| adenoma at | |||||
| 50 | |||||
| Sebaceous carcinomas at 55, 56 | |||||
| M | 44 | MSH2 | Del exon 5 (presumed, patient deceased) | None | |
| F | 33 | MSH2 | c.1980_1981delTA | None | [10] |
| M | 64 | MSH2 | c.2635-3C>G | Colon | |
| carcinoma at 56 | |||||
| F | 78 | MSH2 | c.754C>T | Sebaceous adenoma, NR | |
| F | 65 | MSH6 | NR | none | [11] |
| M | 29 | MSH2 | 1906G>C | none | [6] |
| M | 68 | MSH2 | NR | Prostate | [12] |
| cancer at 58 | |||||
| Sebaceous carcinomas, NR | |||||
| F | 58 | MSH2 | p.Asn263fs | none | [13] |
| F | 54 | MSH2 | NR | Ovarian | [14] |
| carcinoma at 44 | |||||
| Colon carcinoma at 47 | |||||
| F | NR | MSH2 | NR | None | |
| M | 52 | MHS2 | c.2131C>T | Sebaceous carcinoma at 53 | [3] |
| M | 47 | MLH1 | c.2246T>C | None | |
| M | 39 | MSH6 | c.2141C>G | none | |
| F | 42 | MSH2 | c.792+1G>A | Sebaceous adenoma at 47 | |
| F | 23 | MSH2 | c.942+3A>T | Sebaceous adenoma at 49 | |
| F | 60 | MSH2 | c.2063T>G | Endometrial carcinoma at 49 | [15] |
| Breast cancer at 57 | |||||
| NR | NR | MSH6 | c.3261delC | NR | [9] |
| NR | NR | MSH2 | c.1906G>C | NR | |
| F | 65 | MSH2 | delG759 | Ovarian | |
| carcinoma at 42 | |||||
| Colon cancers at 48, | |||||
| 62,65 | |||||
| M | 34 | MSH2 | IVS10+1G>A (presumed, patient deceased, father MSH2+ and had colorectal cancer at 62, paternal aunt MSH2+, endometrial cancer at 38, 2nd paternal aunt | Adrenal cortical carcinoma | [16] |
| MSH2+, endometrial cancer at 49) |
*NR, not reported.
cases of hereditary ACC previously unreported in the literature.
Most cases of LS are caused by mutations in MLH1 or MSH2, with a smaller proportion due to mutations in MSH6, PMS2 or EPCAM [1]. This kindred carries a deletion of exon 5 in MSH2. Among the cases of ACC reported in LS families, MSH2 is clearly overrepresented (17 of 21 pa- tients, 81 %). This predominance has not been previously described. Per our review, six of 20 LS (30 %) patients with ACC also had documented sebaceous adenomas or sebaceous carcinomas, confirming diagnoses of MTS. A splice site mutation causing deletion in exon 5 of MSH2 (c.942+3A>T) has been associated with MTS [15]. Studies suggest that an intact exon 5 may suppress the development of sebaceous skin lesions that arise in MTS [14,16]. We propose that exon 5 of MSH2 may serve as a biological basis for adrenal carcinogenesis.
As multigene panel genetic testing becomes more common, increasing numbers of Lynch syndrome families will be identified. We recommend consideration of adrenal screening for Lynch syndrome patients who have a close relative with ACC, especially those with Muir- Torre syndrome or MSH2 mutations. Ultrasound or MRI screening of the adrenals could be used every one to two years. There is precedence for this strategy in pancreatic cancer screening, where patients with both a genetic predisposition to pancreatic cancer and an affected close relative are offered screening for a low- prevalence but highly lethal malignancy [17].
This case also highlights the complexities of the interpretation of germline and somatic tumor testing. The results may be discordant and can complicate management. The American Society of Clinical Oncology (ASCO) recommends somatic genomic sequencing for patients with advanced or metastatic solid tumors since the presence of certain mu- tations or genomic patterns can direct clinical care [18]. However, sequencing tumor tissue cannot reliably distinguish between somatic and germline changes [19], and may not detect underlying germline variants, as in our patient. In a large-scale retrospective cohort study, 8.1 % of pathogenic germline variants (PGVs) were missed by tumor sequencing [19]. This may be due to different methodologies in somatic vs. germline testing. In addition, next-generation sequencing (NGS) of tumor DNA can fail to detect large or complex mutations or if the tumor specimen has low purity [8]. In a study examining 815 tumor-normal paired samples, a tumor-only sequencing approach could not defi- nitely identify germline changes in cancer-predisposing genes [20]. Furthermore, if the specimen exhibits more than 50 % tumor cellularity, tumor sequencing cannot reliably distinguish between somatic and germline alterations using variant allele fractions [20].
Although somatic testing could potentially identify a pathogenic variant in a gene that has potential germline implications and thus guide germline testing, it is not a replacement for germline testing. This case highlights the importance of separate germline and tumor sequencing in patients who qualify, and careful correlation of results.
Conclusion
Here, we report a case of hereditary ACC in a kindred with Muir- Torre syndrome. Patients with MSH2 mutations appear to be at higher risk of ACC than other LS patients [12], raising consideration of ACC screening in LS kindreds with a family history of ACC. Genetic analysis of the ACC showed intact mismatch repair genes. ASCO guidelines recommend tumor sequencing for all advanced malignancies [18]. In addition to these guidelines, we advocate for the independent role of germline testing and emphasize that somatic tumor sequencing cannot replace germline testing.
Funding sources
No funding sources were secured for this study.
Patient consent
Our patient has signed the Springer/BMC consent form, and the signed form is available from the corresponding author upon request.
Consent to publish
Written informed consent for publication of their details was ob- tained from the patient and our patient has signed a consent to publish form, this signed from can be made available from the corresponding author upon request.
Disclosures
KA and RG have nothing to disclose.
CRediT authorship contribution statement
Kripa Ahuja: Writing - review & editing, Data curation, Investiga- tion, Methodology, Resources, Visualization. Ranjit Goudar: Concep- tualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing - original draft.
Declaration of competing interest
Kripa Ahuja and Ranjit Goudar have no conflicts of interests or disclosures.
Data availability
Data will be made available on request.
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