Microsatellite instability, a well-established driver pathway in colorectal carcinogenesis, can develop in both sporadic and hereditary conditions via different molecular alterations in the DNA mismatch repair (MMR) genes. MMR protein immunohistochemistry (IHC) is currently widely used for the detection of MMR deficiency in solid tumors. The IHC test, however, can show varied staining patterns, posing challenges in the interpretation of the staining results in some cases. Here we report a case of an 80-year-old female with a colonic adenocarcinoma that exhibited an unusual “null” IHC staining pattern with complete loss of all four MMR proteins (MLH1, MSH2, MSH6, and PMS2). This led to subsequent MLH1 methylation testing and next generation sequencing which demonstrated that the loss of all MMR proteins was associated with concurrent promoter hypermethylation of MLH1 and double somatic truncating mutations in MSH2. These molecular findings, in conjunction with the patient’s age being 80 years and the fact that the patient had no personal or family cancer history, indicated that the MMR deficiency was highly likely sporadic in nature. Thus, the stringent Lynch syndrome type surveillance programs were not recommended to the patient and her family members. This case illustrates a rare but important scenario where a null IHC phenotype signifies complex underlying molecular alternations that bear clinical management implications, highlighting the need for recognition and awareness of such unusual IHC staining patterns.
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Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138:2073–2087Google Scholar
Hagen CE, Lefferts J, Hornick JL, Srivastava A (2011) Null pattern of immunoreactivity in a Lynch syndrome-associated colon cancer due to germline MSH2 mutation and somatic MLH1 hypermethylation. Am J Surg Pathol 35:1902–1905CrossRefPubMedGoogle Scholar
Sourrouille I, Coulet F, Lefevre JH, Colas C, Eyries M, Svrcek M et al (2013) Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors. Fam Cancer 12:27–33CrossRefPubMedGoogle Scholar
Mensenkamp AR, Vogelaar IP, van Zelst-Stams WAG, Goossens M, Ouchene H, Hendriks-Cornelissen SJB et al (2014) Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 146:643–646CrossRefPubMedGoogle Scholar
Shia J (2008) Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. J Mol Diagn JMD 10:293–300CrossRefPubMedGoogle Scholar
Airaud F, Küry S, Valo I, Maury I, Bonneau D, Ingster O, et al (2012) A de novo germline MLH1 mutation in a Lynch syndrome patient with discordant immunohistochemical and molecular biology test results. World J Gastroenterol 18:5635–5639CrossRefPubMedPubMedCentralGoogle Scholar
Shia J, Zhang L, Shike M, Guo M, Stadler Z, Xiong X, et al (2013) Secondary mutation in a coding mononucleotide tract in MSH6 causes loss of immunoexpression of MSH6 in colorectal carcinomas with MLH1/PMS2 deficiency. Mod Pathol 26:131–138CrossRefPubMedGoogle Scholar
Cheng DT, Mitchell TN, Zehir A, Shah RH, Benayed R, Syed A et al (2015) Memorial sloan kettering-integrated mutation profiling of actionable cancer targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn JMD 17:251–264CrossRefPubMedGoogle Scholar
Niu B, Ye K, Zhang Q, Lu C, Xie M, McLellan MD, et al (2014) MSIsensor: microsatellite instability detection using paired tumor-normal sequence data. Bioinforma Oxf Engl 30:1015–1016CrossRefGoogle Scholar
Dymerska D, Serrano-Fernández P, Suchy J, Pławski A, Słomski R, Kaklewski K et al (2010) Combined iPLEX and TaqMan assays to screen for 45 common mutations in Lynch syndrome and FAP patients. J Mol Diagn JMD 12:82–90CrossRefPubMedGoogle Scholar
Finn RD, Mistry J, Tate J, Coggill P, Heger A, Pollington JE et al (2010) The Pfam protein families database. Nucleic Acids Res 38:D211–D222CrossRefPubMedGoogle Scholar
Morak M, Heidenreich B, Keller G, Hampel H, Laner A, de la Chapelle A, et al (2014) Biallelic MUTYH mutations can mimic Lynch syndrome. Eur J Hum Genet EJHG 22:1334–1337CrossRefPubMedGoogle Scholar
Elsayed FA, Kets CM, Ruano D, van den Akker B, Mensenkamp AR, Schrumpf M, et al (2015) Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur J Hum Genet EJHG 23:1080–1084CrossRefPubMedGoogle Scholar
Provenzale D, Gupta S, Ahnen DJ, Bray T, Cannon JA, Cooper G et al (2016) Genetic/familial high-risk assessment: colorectal version 1.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw JNCCN 14:1010–1030CrossRefGoogle Scholar