abstract
Objective
To evaluate the risk of
urothelial cancer in the upper urinary tract and the bladder, determine
the contribution from the different mismatch-repair genes and define
clinical characteristics of urothelial cancer in Lynch syndrome.
Methods
The
national hereditary nonpolyposis colorectal cancer registry was used to
identify all 288 Lynch syndrome families in Denmark. Urothelial cancers
that developed in mutation carriers and in their first-degree relatives
were identified, mismatch-repair status was assessed,
clinico-pathologic variables were defined and cumulative life-time risks
were determined.
Results
In total,
48 cancers of the ureter, 34 cancers of the renal pelvis and 54 urinary
bladder cancers developed at a mean age of 61 (24-89) years. The tumors
were typically of high grade, showed loss of mismatch repair protein
expression in 90% of the tumors and microsatellite instability in 23% of
the tumors. Mutations in
MSH2 were overrepresented (73%) and
MSH2 mutation carriers were at significantly increased risk of urinary tract cancer compared individuals with mutations in
MLH1/MSH6.
Conclusions
Cancers
of the upper urinary tract as well as the urinary bladder are included
in the Lynch syndrome tumor spectrum. Urothelial cancers are
predominantly linked to
MSH2 mutations, which suggest that surveillance should be targeted at individuals with mutations herein.
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