TY - JOUR
T1 - Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2
AU - ten Broeke, Sanne W.
AU - van Bavel, Tom C.
AU - Jansen, Anne M.L.
AU - Gómez-García, Encarnca
AU - Hes, Frederik J.
AU - van Hest, Liselot P.
AU - Letteboer, Tom G.W.
AU - Olderode-Berends, Maran J.W.
AU - Ruano, Dina
AU - Spruijt, Liesbeth
AU - Suerink, Manon
AU - Tops, Carli M.
AU - van Eijk, Ronald
AU - Morreau, Hans
AU - van Wezel, Tom
AU - Nielsen, Maartje
N1 - Funding Information:
Funding This work was funded by the Dutch Cancer Society (UL-2012-5515).
Publisher Copyright:
© 2018 AGA Institute
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Background & Aims: Germline variants in mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in older patients than CRCs with variants in other mismatch repair genes. Methods: We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3,000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher exact test. Results: None of the PMS2-associated CRCs contained any somatic variants in the catenin-β1 gene (CTNNB1), which encodes β-catenin, whereas 14 of 24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half the PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%; P =.44) and MSH2 (71.4%; P =.035) than in those associated with variants in PMS2. Conclusions: In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence.
AB - Background & Aims: Germline variants in mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in older patients than CRCs with variants in other mismatch repair genes. Methods: We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3,000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher exact test. Results: None of the PMS2-associated CRCs contained any somatic variants in the catenin-β1 gene (CTNNB1), which encodes β-catenin, whereas 14 of 24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half the PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%; P =.44) and MSH2 (71.4%; P =.035) than in those associated with variants in PMS2. Conclusions: In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence.
KW - Colon Cancer
KW - Genetics
KW - Mismatch Repair
KW - Wnt Signaling
KW - Epithelial Cell Adhesion Molecule/genetics
KW - Humans
KW - Middle Aged
KW - Colorectal Neoplasms/genetics
KW - Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
KW - Male
KW - Mismatch Repair Endonuclease PMS2/genetics
KW - DNA-Binding Proteins/genetics
KW - DNA Mismatch Repair
KW - Germ-Line Mutation
KW - Adult
KW - Female
KW - Aged
KW - MutL Protein Homolog 1/genetics
KW - beta Catenin/genetics
UR - http://www.scopus.com/inward/record.url?scp=85052496554&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2018.05.020
DO - 10.1053/j.gastro.2018.05.020
M3 - Article
C2 - 29758216
AN - SCOPUS:85052496554
SN - 0016-5085
VL - 155
SP - 844
EP - 851
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -