Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer

Vilar, Eduardo; Mork, Maureen E.; Cuddy, Amanda; Borràs, Ester; Bannon, Sarah A.; Taggart, Melissa W.; Jin, Ying; Broaddus, Russell R.; Luthra, Rajyalakshmi; Rodrı́guez-Bigas, Miguel A.; Lynch, Patrick M.; You, Yi Qian Nancy

doi:10.1016/j.cancergen.2014.10.002

Cited by 25 publications

(19 citation statements)

References 28 publications

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“…MSI-H endometrial cancer specimens from 2000–2015 were identified from archived samples in the Gynecologic Oncology tumor bank and Lynch syndrome patient registry. MSI tumor status was determined clinically using a method developed by the Molecular Diagnostic Laboratory at MD Anderson Cancer Center that has been previously described (21) and results were reported in the medical record. Briefly, MSI testing was performed following extraction of DNA from FFPE tumor and normal tissue.…”

Section: Methodsmentioning

confidence: 99%

Immune Microenvironment in Microsatellite-Instable Endometrial Cancers: Hereditary or Sporadic Origin Matters

Pakish

Zhang

Chen

et al. 2017

Clinical Cancer Research

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Purpose Recent studies show that colorectal tumors with high microsatellite instability (MSI-H) have increased immunogenicity and response to immunotherapy compared to microsatellite stable (MSS) tumors. It is not yet clear if MSI-H endometrial cancer (EC) may also benefit from these therapies. It is also unknown whether immune response is equivalent in MSI-H EC with sporadic or inherited Lynch syndrome origins. Experimental Design Multiplexed fluorescent immunohistochemistry (IHC) was used to compare matched MSI-H (n=60) and MSS (n=96) EC specimens by evaluating immune cell populations in tumor and stroma compartments. Sporadic MSI-H and Lynch syndrome-associated (LS) MSI-H EC were also directly compared. Results Increased immune cells were present in stroma of MSI-H EC compared to MSS, including granzyme B+ cells, activated cytotoxic T lymphocytes (CTLs, CD8+granzyme B+), and PD-L1+ cells. Granzyme B+ cells and activated CTLs were also increased in the tumor compartment of MSI-H ECs. Comparing sporadic and LS MSI-H EC showed distinct differences in immune cell populations, indicating that mechanisms underlying microsatellite instability alter immune response. Specifically, LS MSI-H EC showed increased CD8+ cells and activated CTLs in stroma, with reduced macrophages in stroma and tumor compared to sporadic MSI-H. Sporadic MSI-H had increased PD-L1+ macrophages in stroma and tumor compared to LS MSI-H EC. Conclusions MSI-H EC has increased immune cell infiltration compared to MSS EC and the hereditary or sporadic origin of microsatellite instability impacts immune response. Clinical trials to determine the role of immunotherapy in patients with MSI-H EC must evaluate Lynch-related and sporadic MSI-H tumors separately.

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Section: Methodsmentioning

confidence: 99%

Immune Microenvironment in Microsatellite-Instable Endometrial Cancers: Hereditary or Sporadic Origin Matters

Pakish

Zhang

Chen

et al. 2017

Clinical Cancer Research

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“…In 1997 the National Cancer Institute recommended a panel, known as the “panel of Bethesda,” comprising five microsatellites: two mononucleotide repeats (BAT25, BAT26) and three dinucleotide repeats (D2S123, D17S250, D5S346) [ 25 ]. Tumors showing instability at two or more of these repeats (40% of markers) are defined at high instability (MSI-H); those with instability between 20–40% are classified as low instability (MSI-L) [ 26 ]; tumors without alteration (20% or less) are classified as stable (MSS). Subsequently, in order to improve the sensitivity rate and the predictive specificity, Bethesda guidelines were revised and other loci were enclosed in the panel test: BAT-25 and BAT-26 besides three other quasimonomorphic mononucleotide repeats, namely, NR21, NR22, and NR24 [ 27 – 29 ].…”

Section: Lynch Syndrome (Ls)mentioning

confidence: 99%

Novel Implications in Molecular Diagnosis of Lynch Syndrome

Liccardo

Rosa

Izzo

et al. 2017

Gastroenterology Research and Practice

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About 10% of total colorectal cancers are associated with known Mendelian inheritance, as Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). In these cancer types the clinical manifestations of disease are due to mutations in high-risk alleles, with a penetrance at least of 70%. The LS is associated with germline mutations in the DNA mismatch repair (MMR) genes. However, the mutation detection analysis of these genes does not always provide informative results for genetic counseling of LS patients. Very often, the molecular analysis reveals the presence of variants of unknown significance (VUSs) whose interpretation is not easy and requires the combination of different analytical strategies to get a proper assessment of their pathogenicity. In some cases, these VUSs may make a more substantial overall contribution to cancer risk than the well-assessed severe Mendelian variants. Moreover, it could also be possible that the simultaneous presence of these genetic variants in several MMR genes that behave as low risk alleles might contribute in a cooperative manner to increase the risk of hereditary cancer. In this paper, through a review of the recent literature, we have speculated a novel inheritance model in the Lynch syndrome; this could pave the way toward new diagnostic perspectives.

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“…In addition, it is known that a subset of Lynch-associated endometrial cancers may have low levels of MSI (MSI-L). The detection of MSI-L in colorectal cancer does not typically warrant a genetic counseling referral unless there is IHC loss of a MMR protein or the patient has an informative family history (11). …”

Section: Introductionmentioning

confidence: 99%

Clinical Challenges Associated with Universal Screening for Lynch Syndrome–Associated Endometrial Cancer

Bruegl

Ring

Daniels

et al. 2017

Cancer Prevention Research

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Universal testing for Lynch syndrome is now a routine component of the diagnostic work-up of endometrial cancer patients. The purpose of this study was to identify prospectively the barriers to universal screening based on a tissue testing approach (microsatellite instability analysis, immunohistochemistry for DNA mismatch repair proteins, and MLH1 methylation analysis). Endometrial carcinoma patients (n=213) prospectively underwent microsatellite instability and immunohistochemistry testing for expression of DNA mismatch repair proteins. Patients with low (MSI-L) or high (MSI-H) levels of tumor microsatellite instability or immunohistochemical loss of MLH1 (and absent MLH1 methylation), MSH2, MSH6, or PMS2 were referred to a genetic counselor for consideration of germline testing. Six discordances (3.1% of tested cases) between immunohistochemistry and microsatellite instability were identified. Half of these exhibited heterogeneous immunohistochemical loss of MLH1/PMS2 and were microsatellite stable (MSS). Of the remaining cases, one was MSS with immunohistochemical loss of MSH6, one was MSS with immunohistochemical loss of MLH1/PMS2 and absent MLH1 promoter methylation, and one was MSI-H with intact expression of DNA MMR proteins. Four patients had MSI-L tumors with intact immunohistochemical protein expression; the clinical significance of MSI-L in endometrial cancer is unclear. Eight patients did not have germline mutations despite tissue testing suggesting Lynch syndrome. Including cases with insufficient tissue for testing and patients declining tissue or germline testing, we encountered significant barriers to universal screening in 13.6% of screened patients (29/213) that preclude designation of a tumor as sporadic or hereditary.

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Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer

Cited by 25 publications

References 28 publications

Immune Microenvironment in Microsatellite-Instable Endometrial Cancers: Hereditary or Sporadic Origin Matters

Immune Microenvironment in Microsatellite-Instable Endometrial Cancers: Hereditary or Sporadic Origin Matters

Novel Implications in Molecular Diagnosis of Lynch Syndrome

Clinical Challenges Associated with Universal Screening for Lynch Syndrome–Associated Endometrial Cancer

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