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

Abstract

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.

Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes

“…Even though there are few case studies describing a so-called ‘null-phenotype’ ( 2 , 5 ), we could not observe a single case with a loss of expression in all four MMR proteins in our cohort. Furthermore, MSH2 expression was retained in all our dMMR cases, which is in line with other studies investigating the exact pattern of MMR expression in dMMR cancer cases ( 3 – 5 ). Besides the rarely occurring immunohistochemical ‘null-phenotype’, the concurrent loss of MLH1/PMS2 and MSH6 expression seems to be the prevalent expression pattern in dMMR cases with an involvement of both MMR subsystems ( 3 – 5 ).…”

“…Furthermore, MSH2 expression was retained in all our dMMR cases, which is in line with other studies investigating the exact pattern of MMR expression in dMMR cancer cases ( 3 – 5 ). Besides the rarely occurring immunohistochemical ‘null-phenotype’, the concurrent loss of MLH1/PMS2 and MSH6 expression seems to be the prevalent expression pattern in dMMR cases with an involvement of both MMR subsystems ( 3 – 5 ).…”

“…As MLH1/PMS2 and MSH2/MSH6 work together as functional heterodimers (1) and as PMS2 and MSH6 are unstable in absence of MLH1 and MSH2 respectively, there is usually only one DNA MMR subsystem affected in malignancies with dMMR. However, there exist also rare unusual cases with defects in both MMR subsystems, which have been described in recent studies (2)(3)(4)(5)(6) and coincide with our clinical practice. Furthermore, there are also digestive system cancer cases that show a heterogenous loss of MMR protein expression, which is also a rarely studied phenomenon (7)(8)(9).…”

“…As stated, we included different digestive system cancer entities each with a considerable MSI frequency: 300 CRCs, 41 GCs, 9 ampullary cancers and 2 small bowel carcinomas. As the simultaneous deficiency in both MMR subsystems is a rare event – presumably about 1-5% ( 3 , 5 , 6 ), we tried to study a broad variety of cases in order not to miss any cases. Hence, we included a) primary cancers as well as metastases, b) biopsies as well as resected specimens, c) patients with and without neoadjuvant chemotherapy, d) different tumor stages (T1 to T4), and e) different histologic subtypes e.g.…”

“…Plenty is known about the frequency, aetiology, prognostic (15,16) and predictive (17,18) implications of dMMR/MSI-H status. However, there are only few studies focusing on the special subgroup of malignancies with an unusual immunophenotype, namely the loss of expression in both MMR functional heterodimers (MLH1/ PMS2 and MSH2/MSH6) (2)(3)(4)(5)(6). In general, MSI is a frequent phenomenon in different digestive tract cancer entities like colorectal carcinoma (CRC) or gastric cancer (GC), which both contribute extensively to the burden of disease globally (19).…”