TY - JOUR
T1 - The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers
AU - Suerink, Manon
AU - van der Klift, Heleen M.
AU - ten Broeke, Sanne W.
AU - Dekkers, Olaf M.
AU - Bernstein, Inge
AU - Capella Munar, Gabriel
AU - Gomez Garcia, Encarna
AU - Hoogerbrugge, Nicoline
AU - Letteboer, Tom G. W.
AU - Menko, Fred H.
AU - Lindblom, Annika
AU - Mensenkamp, Arjen
AU - Moller, Pal
AU - van Os, Theo A.
AU - Rahner, Nils
AU - Redeker, Bert J. W.
AU - Olderode, Maran
AU - Spruijt, Liesbeth
AU - Vos, Yvonne J.
AU - Wagner, Anja
AU - Morreau, Hans
AU - Hes, Frederik J.
AU - Vasen, Hans F. A.
AU - Tops, Carli M.
AU - Wijnen, Juul T.
AU - Nielsen, Maartje
PY - 2016/4
Y1 - 2016/4
N2 - Purpose: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype. Methods: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally. Results: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC. Conclusions: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-oforigin effect.
AB - Purpose: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype. Methods: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally. Results: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC. Conclusions: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-oforigin effect.
KW - genotype-phenotype correlations
KW - hereditary colon cancer
KW - Lynch syndrome
KW - PMS2
KW - parent-of-origin effect
U2 - 10.1038/gim.2015.83
DO - 10.1038/gim.2015.83
M3 - Article
C2 - 26110232
SN - 1098-3600
VL - 18
SP - 405
EP - 409
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 4
ER -