Colorectal Carcinomas With Isolated Loss of PMS2 Staining by Immunohistochemistry

Alpert, Lindsay; Pai, Reetesh K.; Srivastava, Amitabh; McKinnon, Wendy; Wilcox, Rebecca; Yantiss, Rhonda K.; Arcega, Ramir; Wang, Hanlin L.; Robert, Marie E.; Liu, Xiuli; Pai, Rish K.; Zhao, Lei; Westerhoff, Maria; Hampel, Heather; Kupfer, Sonia S.; Setia, Namrata; Xiao, Shu Yuan; Hart, John; Frankel, Wendy L.

doi:10.5858/arpa.2017-0156-oa

Cited by 23 publications

(16 citation statements)

References 28 publications

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“…use MSI-PCR as a confirmatory test. In fact, isolated loss of PMS2 immunostaining is found in 4% of tumours with MSI [52], and cases with solitary loss of PMS2 or MSH6 protein expression may carry somatic gene variants of these genes [53]. Again, all these observations strengthen our recommendation to use all four MMR proteins.…”

Section: Consensus Recommendations On Msi Testing and How To Measure mentioning

confidence: 58%

ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach

et al. 2019

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Background: Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy. Methods: To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression. Results: The MSI-related definitions, for which a consensus framework was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types. Conclusions: This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1.

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Section: Consensus Recommendations On Msi Testing and How To Measure mentioning

confidence: 58%

ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach

et al. 2019

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“…Tumours with isolated PMS2 loss seem to have specific clinicopathological features. The risk of developing CRC is lower among LS patients carrying germline PMS2 mutations than among LS patients carrying germline mutations in other MMR genes (10-20% by age 70 years, instead of 40-50% with MLH1 or MSH2 mutations) [1]. In addition, CRCs with isolated loss of PMS2 expression showed a lower frequency of histologic features of MSI and a tendency toward aggressive behaviour, which may be related to less immune activation.…”

Section: Discussionmentioning

confidence: 91%

“…This pattern also occurs in most cases of Lynch syndrome (LS) due to MLH1 germline mutation, whereas MSH2/MSH6 loss occurs in LS due to MSH2 germline mutations [3]. In addition to these two more common pattern of MMR protein expression in tumour with MMRD, other less frequent patterns, such as isolated losses of PMS2 and MSH6 also occurred in LS patients due to germline mutations of PMS2 [1] and MSH6 [5,6], respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Mismatch repair proteins deficiency (MMRD) can be studied by different methods in tumour tissue, but the most commonly used in the routine practice are immunohistochemistry (IHC) to analyze the expression of MMR proteins (MLH1, PMS2, MSH2 and MSH6) and/or microsatellite instability (MSI) analysis [ 1 , 2 ]. Tumours with MMRD, in general, loss not only the expression of the protein coded by the altered gene, but also the paired protein in the heterodimer [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Next generation sequencing to decipher concurrent loss of PMS2 and MSH6 in colorectal cancer

et al. 2020

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Background: Immunohistochemistry (IHQ) is commonly used for the detection of mismatch repair proteins deficiency (MMRD). One very infrequent abnormal pattern of MMR protein expression is the loss of PMS2 and MSH6, with intact expression of MLH1 and MSH2. Case presentation: We review the frequency of this MMRD IHC pattern among 108 colorectal (CRCs) and 35 endometrial cancers in our files with loss of expression of at least one protein, and present two CRCs showing loss of PMS2 and MSH6 protein expression (1.9% of CRCs). NGS analysis of these tumours identified PMS2 mutations (R134* germline mutation in one tumour and M1R and c.1239delA somatic mutation in the other) as the primary event and somatic MSH6 mutation (c.3261dupC) as the secondary event in both tumours. Conclusions: This study suggests that Next Generation Sequencing (NGS) tumour analysis should be considered in the algorithm of Lynch syndrome screening to detect MMR gen somatic mutation in inconclusive cases.

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“…A high proportion of colorectal cancer (CRC) cases with isolated PMS2 loss have underlying germline mutations in PMS2 or MLH1 , indicating Lynch syndrome . However, PMS2 loss associated with absent or abnormal MLH1 staining is much more commonly a somatic rather than hereditary phenomenon.…”

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confidence: 99%

Punctate MLH1 mismatch repair immunostaining in colorectal cancer

et al. 2019

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Colorectal Carcinomas With Isolated Loss of PMS2 Staining by Immunohistochemistry

Cited by 23 publications

References 28 publications

ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach

ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach

Next generation sequencing to decipher concurrent loss of PMS2 and MSH6 in colorectal cancer

Punctate MLH1 mismatch repair immunostaining in colorectal cancer

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