TY - JOUR
T1 - MSH2 loss in primary prostate cancer
AU - Guedes, Liana B.
AU - Antonarakis, Emmanuel S.
AU - Schweizer, Michael T.
AU - Mirkheshti, Nooshin
AU - Almutairi, Fawaz
AU - Park, Jong Chul
AU - Glavaris, Stephanie
AU - Hicks, Jessica
AU - Eisenberger, Mario A.
AU - De Marzo, Angelo M.
AU - Epstein, Jonathan I.
AU - Isaacs, William B.
AU - Eshleman, James R.
AU - Pritchard, Colin C.
AU - Lotan, Tamara L.
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/11/15
Y1 - 2017/11/15
N2 - Purpose: Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects. Experimental Design: A total of 1,133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS). Results: Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9–10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (P < 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed MSH2 loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in MSH2. Tumors with MSH2 loss had a higher density of infiltrating CD8 þ lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm 2 ; P ¼ 0.008), and CD8 þ density was correlated with mutation burden among cases with MSH2 loss (r ¼ 0.72, P ¼ 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls. Conclusions: Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
AB - Purpose: Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects. Experimental Design: A total of 1,133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS). Results: Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9–10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (P < 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed MSH2 loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in MSH2. Tumors with MSH2 loss had a higher density of infiltrating CD8 þ lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm 2 ; P ¼ 0.008), and CD8 þ density was correlated with mutation burden among cases with MSH2 loss (r ¼ 0.72, P ¼ 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls. Conclusions: Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
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U2 - 10.1158/1078-0432.CCR-17-0955
DO - 10.1158/1078-0432.CCR-17-0955
M3 - Article
C2 - 28790115
AN - SCOPUS:85034819346
SN - 1078-0432
VL - 23
SP - 6863
EP - 6874
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -