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 history, 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 (6), adrenal cortical carcinoma is associated with Lynch syndrome (2). 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 cases of hereditary ACC, previously unreported in the literature.
Table 1. Characteristics of reported patients with ACC and Lynch syndrome
|
Sex
|
Age at diagnosis of ACC
|
Gene
|
Mutation
|
Lynch-associated cancer
|
Reference
|
1
|
M
|
59
|
MSH2
|
Del exon 5
|
Colon cancer at 49
Sebaceous adenoma at 50
Sebaceous carcinomas at 55, 56
|
|
2
|
M
|
44
|
MSH2
|
Del exon 5 (presumed, patient deceased)
|
|
|
3
|
F
|
33
|
MSH2
|
c.1980_1981delTA
|
none
|
(14)
|
4
|
M
|
64
|
MSH2
|
c.2635-3C>G
|
Colon carcinoma at 56
|
|
5
|
F
|
78
|
MSH2
|
c.754C>T
|
Sebaceous adenoma, NR
|
|
6
|
F
|
65
|
MSH6
|
NR
|
none
|
(15)
|
7
|
M
|
29
|
MSH2
|
1906G>C
|
none
|
(16)
|
8
|
M
|
68
|
MSH2
|
NR
|
Prostate cancer at 58
Sebaceous carcinomas, NR
|
17)
|
9
|
F
|
58
|
MSH2
|
p.Asn263fs
|
none
|
(18)
|
10
|
F
|
54
|
MSH2
|
NR
|
Ovarian carcinoma at 44
Colon carcinoma at 47
|
(19)
|
11
|
F
|
NR
|
MSH2
|
NR
|
None
|
|
12
|
M
|
52
|
MHS2
|
c.2131C>T
|
Sebaceous carcinoma at 53
|
(2)
|
13
|
M
|
47
|
MLH1
|
c.2246T>C
|
None
|
|
14
|
M
|
39
|
MSH6
|
c.2141C>G
|
none
|
|
15
|
F
|
42
|
MSH2
|
c.792+1G>A
|
Sebaceous adenoma at 47
|
|
16
|
F
|
23
|
MSH2
|
c.942+3A>T
|
Sebaceous adenoma at 49
|
|
17
|
F
|
60
|
MSH2
|
c.2063T>G
|
Endometrial carcinoma at 49
Breast cancer at 57
|
(20)
|
18
|
NR
|
NR
|
MSH6
|
c.3261delC
|
NR
|
(10)
|
19
|
NR
|
NR
|
MSH2
|
c.1906G>C
|
NR
|
|
20
|
F
|
65
|
MSH2
|
delG759
|
Ovarian carcinoma at 42
Colon cancers at 48, 62, 65
|
|
21
|
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 MSH2+, endometrial cancer at 49)
|
Adrenal cortical carcinoma
|
(21)
|
*NR, not reported.
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 patients, 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 a deletion in exon 5 of MSH2 (c.942+3A>T) has been associated with MTS (20). Studies suggest that an intact exon 5 may suppress the development of sebaceous skin lesions that arise in MTS (19,21). We propose that exon 5 of MSH2 may serve 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(22). 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 (23).
This case also highlights the complexities of 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 mutations or genomic patterns can direct clinical care (24). However, sequencing tumor tissue cannot reliably distinguish between somatic and germline changes (25), 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 (25). This may be due to different methodology 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 (9). In a study examining 815 tumor-normal paired samples, a tumor-only sequencing approach could not definitely identify germline changes in cancer-predisposing genes (26). Furthermore, if the specimen exhibits more than 50% tumor cellularity, tumor sequencing cannot reliably distinguish between somatic and germline alterations using variant allele fractions (26).
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.