In colorectal cancers (CRCs) with tumour mismatch repair (MMR) deficiency, genes involved in the host immune response that contain microsatellites in their coding regions, including beta-2-microglobulin (B2M), can acquire mutations that may alter the immune response, tumour progression and prognosis. We screened the coding microsatellites within B2M for somatic mutations in MMR-deficient CRCs and adenomas to determine associations with tumour subtypes, clinicopathological features and survival. Incident MMR-deficient CRCs from Australasian Colorectal Cancer Family Registry (ACCFR) and the Melbourne Collaborative Cohort Study participants (n = 144) and 63 adenomas from 41 MMR gene mutation carriers from the ACCFR were screened for somatic mutations within five coding microsatellites of B2M. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival by B2M mutation status were estimated using Cox regression, adjusting for age at CRC diagnosis, sex, AJCC stage and grade. B2M mutations occurred in 30 (20.8%) of the 144 MMR-deficient CRCs (29% of the MLH1-methylated, 17% of the Lynch syndrome and 9% of the suspected Lynch CRCs). No B2M mutations were identified in the 63 adenomas tested. B2M mutations differed by site, stage, grade and lymphocytic infiltration although none reached statistical significance (p > 0.05). The HR for overall survival for B2M mutated CRC was 0.65 (95% CI 0.29–1.48) compared with B2M wild-type. We observed differences in B2M mutation status in MMR-deficient CRC by tumour subtypes, site, stage, grade, immune infiltrate and for overall survival that warrant further investigation in larger studies before B2M mutation status can be considered to have clinical utility.
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This work was supported by Grant UM1 CA167551 from the National Cancer Institute and through cooperative agreements with Australasian Colorectal Cancer Family Registry (U01 CA074778 and U01/U24 CA097735) and was conducted under Colon-CFR approval C-AU-1014-01. The Melbourne Collaborative Cohort Study for colorectal cancer was funded by NHMRC project Grant 509348 (PI-Dallas English) “Risk Factors for Molecular Subtypes of Colorectal Cancer”. Aung K. Win is an Australian National Health and Medical Council (NHMRC) Early Career Fellow. Melissa C. Southey is a NHMRC Senior Research Fellow. Mark A. Jenkins is a NHMRC Senior Research Fellow. John L. Hopper is a NHMRC Senior Principal Research Fellow and Distinguished Visiting Professor at Seoul National University, Korea. Christophe Rosty is the Jass Pathology Fellow. Daniel D. Buchanan is a University of Melbourne Research at Melbourne Accelerator Program (R@MAP) Senior Research Fellow and NHMRC R.D. Wright Career Development Fellow.
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Conflict of interest
The authors declare they hold no conflict of interest with respect to this work.
The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Cancer Family Registries, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the Cancer Family Registry. Authors had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript.
Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. doi:10.1002/ijc.29210CrossRefPubMedGoogle Scholar
Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260(5109):816–819CrossRefPubMedGoogle Scholar
Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E (2010) Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer 46(15):2788–2798. doi:10.1016/j.ejca.2010.05.009CrossRefPubMedGoogle Scholar
Ligtenberg MJ, Kuiper RP, Chan TL et al (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet 41(1):112–117. doi:10.1038/ng.283CrossRefPubMedGoogle Scholar
Herman JG, Umar A, Polyak K et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95(12):6870–6875CrossRefPubMedPubMedCentralGoogle Scholar
Haraldsdottir S, Hampel H, Tomsic J et al (2014) Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology 147(6):1308-16 e1. doi:10.1053/j.gastro.2014.08.041CrossRefGoogle Scholar
Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA et al (2014) Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 146(3):643-6 e8. doi:10.1053/j.gastro.2013.12.002CrossRefGoogle Scholar
Buchanan DD, Rosty C, Clendenning M, Spurdle AB, Win AK (2014) Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome). Appl Clin Genet 7:183–193. doi:10.2147/TACG.S48625PubMedPubMedCentralGoogle Scholar
Yamamoto H, Yamashita K, Perucho M (2001) Somatic mutation of the beta2-microglobulin gene associates with unfavorable prognosis in gastrointestinal cancer of the microsatellite mutator phenotype. Gastroenterology 120(6):1565–1567CrossRefPubMedGoogle Scholar
Giles GG, English DR (2002) The Melbourne collaborative cohort study. IARC Sci Publ 156:69–70PubMedGoogle Scholar
Newcomb PA, Baron J, Cotterchio M et al (2007) Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomark Prev 16(11):2331–2343CrossRefGoogle Scholar
Walsh MD, Buchanan DD, Pearson SA et al (2012) Immunohistochemical testing of conventional adenomas for loss of expression of mismatch repair proteins in Lynch syndrome mutation carriers: a case series from the Australasian site of the colon cancer family registry. Mod Pathol 25(5):722–730. doi:10.1038/modpathol.2011.209CrossRefPubMedPubMedCentralGoogle Scholar
Ripberger E, Linnebacher M, Schwitalle Y, Gebert J, von Knebel Doeberitz M (2003) Identification of an HLA-A0201-restricted CTL epitope generated by a tumor-specific frameshift mutation in a coding microsatellite of the OGT gene. J Clin Immunol 23(5):415–423CrossRefPubMedGoogle Scholar
Schwitalle Y, Linnebacher M, Ripberger E, Gebert J, von Knebel Doeberitz M (2004) Immunogenic peptides generated by frameshift mutations in DNA mismatch repair-deficient cancer cells. Cancer Immun 4:14PubMedGoogle Scholar
Echterdiek F, Janikovits J, Staffa L et al (2016) Low density of FOXP3-positive T cells in normal colonic mucosa is related to the presence of beta2-microglobulin mutations in Lynch syndrome-associated colorectal cancer. Oncoimmunology 5(2):e1075692 doi:10.1080/2162402X.2015.1075692CrossRefPubMedGoogle Scholar