DOI: 10.1200/po-26-00974 ISSN: 2473-4284
Redefining the
EPCAM
Phenotype: Deletion Architecture Determines Lynch Syndrome Cancer Risk
Kristin Kohler, Ashley P.L. Marsh, Felicia Hernandez, Carolyn Horton, John Michael O. Ranola, Heather Hampel, Michael J. Hall
Purpose
To characterize the cancer phenotype and clinical presentation across molecularly distinct
EPCAM
deletion subgroups and determine how the phenotype varies with
MSH2
involvement.
Methods
We retrospectively evaluated 662 unrelated probands undergoing hereditary cancer multigene panel testing (MGPT) with isolated
EPCAM
full-gene deletions (n = 22), isolated
EPCAM
3' deletions (n = 96), contiguous
EPCAM
full-gene deletions extending into
MSH2
(n = 64), contiguous
EPCAM
3' deletions extending into
MSH2
(n = 116),
MSH2
gross deletions (n = 155), and
MSH2
nonsense/frameshift (ns/fs) variants (n = 209). Lynch syndrome (LS)–associated cancer prevalence, tumor spectrum, and PREMM5 scores were compared across cohorts. Multivariable logistic regression estimated cancer-specific associations relative to a MGPT-negative reference cohort.
Results
Isolated
EPCAM
full-gene deletions, comprising 18.6% of observed isolated
EPCAM
deletions, were not significantly associated with LS-associated cancers. The LS-associated cancer prevalence was 13.6% in this cohort, compared with 54.6% with isolated
EPCAM
3' deletions and 64.1%-72.2% in
MSH2
-involving cohorts (
P
< .001). Relative to MGPT-negative individuals, isolated
EPCAM
3' deletions were strongly associated with colorectal cancer (odds ratio [OR], 17.59;
P
< .001) but not endometrial cancer (OR, 0.76;
P
= .790).
MSH2
-involving cohorts demonstrated strong associations with both colorectal (ORs, 8.50-16.03;
P
< .001) and endometrial cancers (ORs, 17.31-30.47;
P
< .001).
Conclusion
These findings provide new insights into the molecular and clinical heterogeneity of germline deletions involving
EPCAM
. Expanded detection across the full
EPCAM
gene and its 3' region distinguishes isolated full-gene deletions, which do not disrupt downstream
MSH2
and are not associated with LS phenotypes, from isolated 3' deletions with a colorectal-predominant phenotype, and contiguous
EPCAM-MSH2
deletions with an
MSH2
-like LS phenotype. Precise delineation of
EPCAM
deletion boundaries and
MSH2
involvement define three clinically relevant risk groups and support more precise risk assessment, counseling, and surveillance.