Intraductal Carcinoma of the Prostate in the Absence of HighGrade Invasive Carcinoma Represents a Molecularly Distinct Type ofin situ Carcinoma Enriched with Oncogenic Driver Mutations

Intraductal Carcinoma of the Prostate in the Absence of High
Grade Invasive Carcinoma Represents a Molecularly Distinct Type of
in situ Carcinoma Enriched with Oncogenic Driver Mutations:

ABSTRACT

Intraductal
carcinoma of the prostate (IDC‐P) most often appears associated
with high grade invasive prostate carcinoma (PCa), where it is
believed to represent retrograde spread. However, IDC‐P rarely
occurs as an isolated finding at radical prostatectomy or with
concurrent low grade (Grade Group 1) invasive carcinoma. We
hypothesized that isolated IDC‐P (iIDC‐P) in these unusual cases
may represent a distinct in situ lesion and
molecularly profiled 15 cases. iIDC‐P was characterized by copy
number alteration profiling and targeted next generation sequencing
in cases with sufficient tissue (N=7). Immunohistochemistry for
PTEN and ERG were performed on the total cohort (N=15), where areas
of iIDC‐P and associated invasive disease were evaluated separately
(N=9). By copy number profiling, iIDC‐P alterations were similar to
those previously described in high grade invasive PCa
(PTEN, RB1, and
CHD1 loss; MYC gain).
However, in four cases, targeted sequencing revealed a striking
number of activating oncogenic driver mutations in MAPK and PI3K
pathway genes, which are extraordinarily rare in conventional PCa.
In addition, pathogenic mutations in DNA repair genes were found in
two cases of iIDC‐P (BRCA2, CHEK2,
CDK12) and other known PCa‐associated mutations
(FOXA1, SPOP) in two cases. Overall, ERG was
expressed in 7% (1/15) of the iIDC‐P lesions and PTEN was lost in
53% (8/15). Discordance for ERG or PTEN status between IDC‐P and
the low grade PCa was observed in five of nine cases, with intact
PTEN in the invasive tumor and PTEN loss in IDC‐P in four. Despite
a copy number alteration profile similar to conventional PCa,
iIDC‐P is enriched with potentially targetable oncogenic driver
mutations in MAPK/PI3K genes. Based on PTEN and ERG status, iIDC‐P
is not likely a precursor to the associated low grade invasive PCa,
but represents a molecularly unique in situ
tumor of unclear clinical significance.