Mismatches in Mismatch Repair: Navigating Discordant MMR/MSI Test Results

Introduction

Testing for mismatch repair (MMR) deficiency and/or microsatellite instability (MSI) involves immunohistochemistry (IHC), polymerase chain reaction (PCR)-based assays, and next-generation sequencing (NGS). Currently, the three main testing approaches are IHC for the MMR proteins, PCR-based MSI assays, and NGS panels that can determine both MSI status and pathologic mutations in the MMR genes. This article compares these methods and offers guidance for resolving conflicting results.

Background

The DNA MMR system maintains genomic fidelity by correcting base substitution mismatches and insertion-deletion loops that arise during DNA replication and recombination. This process is primarily mediated by a heterodimeric protein complex made of the key proteins MLH1, MSH2, MSH6, and PMS2. Germline or somatic inactivation of the genes encoding these proteins leads to deficient MMR (dMMR), resulting in the accumulation of somatic mutations at a rate several orders of magnitude higher than in MMR-proficient cells. The molecular hallmark of this hypermutable phenotype is MSI, characterized by length variations in short tandem DNA repeats. Clinically, dMMR/MSI status has emerged as a critical marker of potential response and eligibility for immune checkpoint inhibitor (ICI) therapy.

Methods for MMR/MSI Detection

MMR protein detection via IHC is a commonly used, fast, and inexpensive method for assessing MMR status in FFPE tumor tissue. It works by detecting four key MMR proteins: MLH1, PMS2, MSH2, and MSH6, which function as obligate heterodimers. MLH1 pairs with PMS2, and MSH2 pairs with MSH6. Loss of MLH1 leads to loss of PMS2, and loss of MSH2 leads to loss of MSH6; however, the reverse is not true. Interpretation involves determining whether nuclear expression of these four proteins is completely lost in tumor cells, as assessed by IHC, relative to adjacent nontumor cells, which serve as the internal positive control. A tumor is classified as MMR-proficient (pMMR) if all four proteins show intact nuclear staining in the tumor cells. Conversely, a tumor is classified as dMMR if there is a complete and unequivocal loss of nuclear staining for one or more MMR proteins in tumor cells. Using MMR IHC has several advantages, including a short turnaround time (typically one to two days), relative affordability, and broad availability in most laboratories.

Additionally, MMR IHC identifies the likely mutated MMR gene, enabling targeted germline testing. Its main drawback is that it assesses protein presence rather than function, which can lead to a false-negative report of pMMR, especially when there is a missense mutation in the C-terminus of the MMR gene. Other issues include loss of MMR protein expression resulting from poor fixation or epitope-escaping variants, as well as heterogeneous staining. Finally, there is a lack of standardized protocols between laboratories. Nevertheless, MMR IHC remains a workhorse for MMR/MSI screening, given its speed and informative output.¹

MSI testing assays evaluate for the functional consequences of MMR deficiency. Some of the PCR-based tests do this by comparing the mutational status of five or more small microsatellite repeats in the patient’s tumor DNA with that in their normal tissue. In contrast, some newer PCR-based assays and nearly all NGS-based assays use only tumor tissue, typically employing up to 13 microsatellite markers with PCR-based methods and hundreds to thousands of microsatellite markers with NGS-based assays. Limitations of PCR-based MSI testing include the requirement for matched normal tissue, longer turnaround times, and varying sensitivity across different tumor types. While PCR-based MSI testing is mostly concordant with MMR IHC in colorectal cancer, lower concordance has been observed in endometrial cancer.^2,3 The concordance with MMR IHC in less frequently tested tissue types, such as the upper GI tract, prostate, and ovary, remains unclear. The four most common PCR-based MSI testing assays are compared in Table 1.

Table 1. PCR-based MSI assays at a glance: legacy and contemporary options with key features.

NGS-based assays can also be used to test for MSI. Common NGS-based MSI algorithms are MSISensor and MANTIS, which are designed to detect instability across multiple loci. Moreover, NGS assays can be efficiently designed to sequence the MMR genes, enabling simultaneous identification of pathogenic variants in one or more MMR genes. NGS assays can also simultaneously assess for pathologic variants in BRAF V600E and POLE/POLD1. Finally, NGS assays can provide the tumor mutational burden (TMB) of a specimen. NGS-based MSI testing provides a comprehensive genomic view from a single test and is particularly efficient when patients require simultaneous large-panel NGS-based DNA assays for tumor profiling.⁴ The performance of MSI testing with NGS-based assays depends on the panel design and validation; however, modern datasets demonstrate noninferiority to IHC and strong concordance across various tumor types.^5,6 Real-world and pathological series also document rare cases that each modality can miss, reinforcing the need for orthogonal testing in equivocal scenarios.^5,7 Each method for MMR/MSI testing is compared in Table 2.

Table 2. Comparison of methods for MMR/MSI testing.

Since the first reports of MSI in 1993 and the launch of the Bethesda panel in 1997,^8–11 MMR/MSI testing has evolved from a niche hereditary cancer screen to a pan-cancer companion diagnostic that guides chemotherapy choices and, critically, eligibility for ICIs. Early comparisons of IHC and PCR in colorectal cohorts showed low discordance (approximately 1% to 3%), but these studies relied on suboptimal methods, notably 2-antibody IHC (MLH1/MSH2) and dinucleotide-heavy PCR panels; so microsatellite instability-high (MSI-H) tumors with isolated PMS2 or MSH6 loss were often mislabeled as pMMR.^12,13 Transitioning to 4-antibody IHC and mononucleotide-rich PCR improved sensitivity; Hatch et al. highlighted this shift and the need for mononucleotide markers.^14,15

Contemporary data reveal that "discordance" depends on technique, interpretation, and tumor biology. Real-world rates range from well below 1% in tightly controlled series to double-digit levels when initial reads and community practice are considered; one study found 10% misclassification among locally called dMMR/MSI-H metastatic colorectal cancer (mCRC) cases and linked these errors to primary ICI nonresponse.¹⁶ Other series note modest cross-platform assay discordance,¹⁷ while an upper-bound report of 19.3% underscores how workflow and context can inflate discrepancies.¹⁸ Rates may be higher outside CRC (e.g., endometrial cancer), where patterns like isolated MSH6 loss are more common.¹⁹ Overall, discordance is not a biological constant, but rather a function of assay design, pathologist review rigor, and cohort heterogeneity, which suggests the need for orthogonal testing and expert adjudication when results do not align.

Currently, the causes of discordant results can be systematically categorized into four major groups: (1) technical and interpretive artifacts; (2) differences in phenotypic (IHC) and genotypic (PCR/NGS) assays; (3) multiple primary tumors; and (4) idiopathic causes. These scenarios are ordered from the most common to the rarest causes of discordance. The first three scenarios represent resolvable discordance. In contrast, the fourth scenario, although likely rare, is an area that has not received significant attention and currently lacks a straightforward, protocol-driven approach.

Technical and interpretive artifacts include:

• Suboptimal fixation: This can lead to weak or absent MMR IHC staining, resulting in an erroneous interpretation of protein loss. In larger tissue samples, a specific area with poor formalin fixation may occur (typically in the center of the tissue), mimicking focal clonal loss of MMR proteins. Typically, this area does not stain with any of the MMR proteins, and if any normal tissue is present, the normal tissue (internal control) will also show loss of MMR IHC staining.
• Low tumor cellularity: This can cause false-negative microsatellite stable (MSS) results in PCR/NGS by masking the unstable microsatellite alleles.²⁰
• Prior chemo/radiation therapy: This can induce MMR protein expression loss, particularly MSH6, creating a dMMR/MSS phenotype that may not reflect the patient’s tumor baseline status.^21,22 When feasible, assess pretreatment tissue. If only post-treatment tissue is available and the results are unexpected, confirm the results with an orthogonal method or an alternative block.²³
• Interpretive error: Subjective IHC interpretation and misinterpretation of MSI-PCR electropherograms contribute to interpretive discordance. Consensus conferences or experienced colleagues can provide valuable assistance. Misinterpreting "intact" IHC staining, when there is heterogeneous loss, can lead to false negatives.
• IHC antibody clone-specific issues: Rare germline polymorphisms can alter the epitope recognized by a specific antibody clone, leading to false protein loss. A known example is the MLH1 p.V384D variant, which is missed by the MLH1 G168-15 antibody clone.²³

Less Common Patterns of MMR IHC Loss

Heterogeneous Loss of Expression of One or More of the MMR IHC Proteins

In contrast to the binary classification of MMR protein expression as either uniformly intact or completely absent, a subset of tumors exhibits heterogeneous staining for one or more MMR proteins. Heterogeneous MMR protein expression can manifest in several distinct patterns, specifically: 

• Subclonal: geographically distinct region(s) of intact and lost staining
• Focal: small clusters of cells with loss
• Zonal: distinct areas or patches within the tumor where the MMR protein is absent
• Mosaic: intermixed single cells with variable staining

Some laboratories assess only MMR protein expression by IHC without concurrent MSI testing by PCR or NGS. A large retrospective study of more than 4,400 patients found that approximately 50% of cases with heterogeneous IHC loss were MSI-H by PCR, whereas the remaining cases were MSS or, less frequently, microsatellite instability-low (MSI-L).²⁴ Patients with heterogeneous MMR protein loss, therefore, have approximately a 50% chance of being MSI-H and eligible for ICI therapy. This means that all patients with heterogeneous MMR protein loss on IHC require microsatellite testing (PCR or NGS), specifically sampling the area with MMR IHC loss.^2,25 Heterogeneous loss also nearly doubles the risk of the patient having Lynch syndrome, necessitating appropriate germline testing and follow-up.¹⁹

Heterogeneous MMR IHC With Synchronous MSI-H Results

Microdissection-based studies demonstrate that IHC-negative foci often harbor MSI-H and/or driver events, such as MLH1 methylation or an MSH6 frameshift mutation. At the same time, the adjacent IHC-intact areas are MSS, confirming biologic subclonality.²⁶ These findings indicate that the heterogeneous patterns of MMR protein expression reflect genuine intratumoral molecular diversity rather than a staining artifact; therefore, reporting heterogeneous loss and the pattern explicitly (e.g., "subclonal MSH6 loss in approximately 10% of tumor cells") helps drive appropriate follow-up.

Heterogeneous MMR IHC With Synchronous MSI-L or MSS Results

Interpreting MMR/MSI testing in patients with heterogeneous MMR protein loss is challenging, particularly for determining eligibility for immune checkpoint therapy. If circling an area for MSI-testing, one must circle an area with MMR IHC loss. When reviewing MSI testing results, it is critical to determine whether the area with MMR IHC loss was tested. If only an intact MMR IHC area was tested for MSI, retesting the area with the greatest MMR IHC loss using PCR- or NGS-based MSI is recommended.
Suppose concordant or follow-up PCR-based MSI testing of the areas with MMR protein loss shows MSS or MSI-L. In that case, further NGS testing of the tumor (specifically the area of loss) for MSI status and pathogenic MMR gene mutations can be considered. If NGS testing classifies the tumor as MSI-H and/or identifies two pathogenic MMR variants (or one variant and with loss of heterozygosity [LOH] of that gene), this supports an MSI-H classification of the tumor. Conversely, if NGS still classifies the tumor as MSS and no pathogenic mutations in MMR genes are found, a final interpretation of MSS classification is supported; however, there is limited information on how these rare patients respond to immune checkpoint inhibition, highlighting the need for further studies.

Complete Loss of All Four MMR Proteins on IHC: The "Null" Phenotype

Although rare, the complete absence of all four MMR proteins is termed the null phenotype. This complex pattern can result from concurrent alterations in both the MLH1 and MSH2 pathways, such as a germline MSH2 mutation combined with somatic MLH1 promoter hypermethylation²⁷; however, calling this phenotype dMMR based solely on IHC staining is not advised. Other studies should be done, including the use of different antibody clone(s), MLH1 promoter methylation assays, and/or an NGS-based panel to support an interpretation of a null phenotype.

Discordance Due to Differences in Phenotypic (IHC) and Genotypic (PCR/NGS) Assays

In these cases, the interpretation of each assay is correct; however, the discordance arises from whether the assay evaluates protein expression or genetic mutations at the DNA level.

pMMR by IHC/MSI-H by Molecular Testing:

• pMMR can arise when an MMR gene harbors a mutation that abrogates its DNA repair function but does not prevent the production of a full-length, antigenically intact protein. These are typically non-truncating C-terminal missense mutations, with the classic example seen in MSH6.^25,26
• Pathogenic mutation in the exonuclease domain of DNA polymerase epsilon (POLE) or delta 1 (POLD1). These mutations create an ultramutated phenotype. The majority of POLE mutant tumors are MSS; however, some can have secondary MSI-H due to overwhelming the microsatellite repair system.²⁸ In these cases, where the MMR proteins are intact and no pathogenic mutations are present, the IHC result will be pMMR. Additionally, pathogenic POLE-mutant cancers can lead to secondary mutations in the MMR genes, resulting in an MSI-H phenotype with dMMR; however, these cases may exhibit atypical loss patterns on MMR IHC, which can be a clue to a POLE mutation.
• Noncanonical Gene Involvement: The standard four-protein IHC panel only assesses the core MMR proteins; however, the MMR machinery involves other gene products, including MSH3, PMS1, MLH3, and EXO1.^30–32 Pathogenic mutations in these genes may cause MMR dysfunction and an MSI-H phenotype, which PCR detects; however, IHC for the main four proteins is normal (pMMR).

dMMR by IHC/MSS by Molecular Testing:

• MSH6 Deficiency: The primary biological driver of this phenotype is often pathologic variants in MSH6, which lead to nonsense-mediated decay of MSH6 RNA and loss of MSH6 protein expression. Currently, it is thought that the loss of MSH6 gene expression leads to a less profound MSI phenotype, characterized by mutations primarily in mononucleotide repeats and smaller allelic shifts that may fall below the detection threshold of standard PCR panels, resulting in an MSS or MSI-L result.²⁹ In discordant cases with isolated MSH6 loss but MSS or only minimal microsatellite shifts, which is particularly common in endometrial carcinoma and may also be seen in post-treatment specimens, NGS-based MSI detection may still identify MSI when IHC or PCR-MSI is falsely negative.^25,29
  • Please see the Tumor-Specific Considerations section (Endometrial Carcinoma) below for additional discussion and assay-performance considerations in this setting.

Multiple Primary Tumors

In this scenario, a primary tumor may be correctly identified as dMMR/MSI-H. Still, a subsequent biopsy of a metastatic lesion for MMR/MSI analysis may sample a metastasis from a second, synchronous, or metachronous primary tumor with pMMR/MSS. Geurts et al. found that multiple primary tumors accounted for 23% (3 of 13) of their initial discordant cases, none of whom benefited from ICI therapy, highlighting this as a critical diagnostic pitfall.³³ As blood-based liquid biopsies are increasingly utilized, many of which test for MSI status, consideration of multiple primary tumors is necessary when there is discordance between MMR/MSI testing in the presumed primary tumor and the liquid biopsy results.

Idiopathic Discordance

Discordant cases that are dMMR or MSI-H but lack two pathogenic MMR gene variants warrant a systematic investigation. Initially, one must confirm the adequacy of internal controls for MMR IHC. Subsequently, consultation with a molecular pathologist is crucial to determine whether the NGS assay provides evidence for a "second hit," such as LOH or homozygous deletion in the MMR gene, corresponding to the protein loss observed on IHC.

However, discrepancies may persist because not all NGS panels are designed or validated to detect LOH, homozygous deletions, large structural variants, copy number changes, or deep intronic splice variants.³⁴ Beyond these assay limitations, other biological mechanisms can potentially cause MMR deficiency.³² For example, upregulation of specific microRNAs can transcriptionally silence MMR genes,³⁵ while pathogenic variants in related genes, such as EXO1, can disrupt the repair complex and induce an MSI-H phenotype.³⁴ Finally, preanalytical factors, including prolonged tumor ischemia, delayed fixation, or hypoxia, can cause artifactual loss of MMR protein expression, mimicking a true dMMR result.³⁶

Approach to Discordant Cases:

• Expert Review: All discordant or ambiguous results should undergo expert pathology review to rule out interpretive errors or technical artifacts, such as poor fixation.
• Consider the Clinical Context: Account for prior neoadjuvant therapy, which can lead to loss of MMR protein. Whenever possible, test pretreatment tissue.
• Report heterogeneous MMR IHC loss: Describe the pattern and consider microdissection-based MSI testing on the area with MMR protein loss.^2,37
• Discuss at a Molecular Tumor Board: Complex cases benefit from multidisciplinary input to arrive at an integrated diagnosis.
• Final Clinical Interpretation: After excluding resolvable causes, any definitive evidence of MMR deficiency (either dMMR by IHC or MSI-H by PCR/NGS) should be considered a positive result for determining eligibility for ICI therapy.²

A suggested approach to interpreting discordant or unusual MMR/MSI patterns, along with possible next steps, is covered in Table 3.

Table 3. Interpreting discordant or unusual MMR/MSI result patterns and possible next steps:

Tumor-Specific Considerations:

• Colorectal Carcinoma: IHC, PCR, and NGS are well-validated and accepted methods that offer largely concordant results²; however, combining two or more methods will help to identify microsatellite repair-deficient tumors that can be missed using only one method alone.^24,38
• Gastroesophageal and Small Bowel Carcinoma: Contrary to previous guidance,² a recent large-scale study⁵ demonstrated that NGS-based MSI testing is noninferior to MMR IHC and PCR-based MSI testing in these tumor types.
• Endometrial Carcinoma: Testing endometrial carcinomas solely with PCR-based MSI testing is no longer recommended,² as multiple studies have demonstrated that it lacks sensitivity in these types of tumors.^6,38,39 Previous guidelines² also advised against using NGS-based MSI testing alone; however, a 2024 study showed that a novel NGS-based MSI detection method (MSIPeak) exhibited higher sensitivity than PCR for detecting small 1- or 2-base-pair deletions that can characterize MSI in endometrial cancer.⁴⁰ Indeed, an NGS-first strategy⁴¹ in endometrial cancer is emerging as potentially more efficient and cost-effective, as it can simultaneously determine MSI status, screen for Lynch syndrome, and provide the complete molecular classification (POLE, TP53) now required for risk stratification. Nevertheless, MMR IHC remains a suitable initial test; however, pathologists interpreting MMR IHC in endometrial cancer patients must be vigilant about identifying and reporting heterogeneous loss of one or more of the MMR proteins, as this pattern of dMMR appears to be more prevalent in endometrial cancers.²⁵
• Prostate Cancer: Limited evidence suggests that the Promega and Bethesda MSI-PCR panels have inferior sensitivity when applied to prostate cancer, with one study showing a sensitivity of only 72.4%.⁴² In contrast, expanded NGS-based panels that interrogate a larger number of microsatellite loci appear to perform significantly better, with reported sensitivities ranging from 93.1% to 96.6%.⁴² Thus far, MMR-IHC appears to be an effective screening method for prostate cancer.^43,44 Nevertheless, as many prostate cancers are not routinely screened with MMR IHC and/or PCR-based MSI testing, additional studies will be needed to determine which methods provide the most effective initial test and how they compare with one another.
• Other solid tumors: Utilize both MMR IHC and a validated MSI-testing method; any dMMR/MSI-H result can guide tumor-agnostic pembrolizumab eligibility.^45–47

Current recommendations suggest that any definitive evidence of MMR deficiency, as determined by either a protein-based assay (IHC) or a DNA-based assay (PCR or NGS), should be considered a positive result for ICI eligibility, regardless of discordant results.^2,48 This pragmatic approach, which prioritizes treatment access for all potentially eligible patients, stems from an appreciation of the complexities inherent in cancer biomarker testing. Nevertheless, all discordant results should be reviewed, ideally in a molecular tumor board setting, to exclude resolvable causes like technical artifacts or the effects of neoadjuvant therapy before a final treatment decision is made.

Over the past two decades, the field has moved away from the assumption that phenotypic (IHC) and genotypic (PCR/NGS) assays are interchangeable. Indeed, recent studies confirm that each test can identify dMMR cases that the other misses.^5,24 Instead, these tests are now understood as complementary diagnostic tools, as each provides distinct biological information and has unique weaknesses that different methodologies can often compensate for; however, this creates a clinical and economic dilemma. While using multiple tests can identify the greatest number of patients who may benefit from ICI therapy, this comes at a higher financial cost. For instance, a recent study estimated that over 1,100 patients would require NGS-based MSI testing to identify one MSI-H case that IHC would miss. In contrast, nearly 500 patients would require IHC to identify one dMMR case missed by NGS.5 Similarly, these numbers were comparable between MMR IHC and PCR-based MSI testing²⁴; therefore, as testing algorithms are developed, those who make them must strike a balance between minimizing cost and maximizing the identification of truly microsatellite-deficient cases. (See Figure 1 for an example workflow.) The future of MMR/MSI testing is shifting beyond the search for a single "best test" toward the development of tumor-specific, integrated diagnostic algorithms that balance cost with the critical need to maximize the identification of all truly microsatellite-deficient tumors.

Figure 1: Example workflow that provides high sensitivity for detecting microsatellite repair deficiency while minimizing cost and potential delays in results. ^§ Testing must be performed on an adequate sample, which has at least 50 to 100 viable invasive cancerous cells present and some background stroma/mucosa, which serves as a positive internal control. Avoid interpreting samples that underwent strong-acid decalcification, as this can destroy MMR antigens. If necessary, EDTA-based decalcification is preferred. The current best practice is to test the initial diagnostic biopsy before any chemotherapy and/or radiation therapy has been given to the patient. Chemoradiation has been shown to induce artificial reduction or loss of MSH6 expression.^{21,22  †} If available, use a different block with cancerous cells present. If no additional block is available, attempt PCR-based or NGS-based MSI testing on the block. ^* LS-associated cancers include colorectal, endometrial, gastric, ovarian, pancreatic, ureter and renal pelvis, biliary tract, glioblastoma, small bowel, and sebaceous gland adenomas and keratoacanthomas. ^** MSI-H histology is defined by the presence of tumor-infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous and/or signet ring differentiation, or medullary growth pattern. ^*** The last two criteria must be identified by the treating clinical team, with the responsibility for ordering MSI testing likely falling on the medical oncologist. ^‡ Either PCR-based and/or NGS-based testing can be utilized based on factors such as availability and cost, as it may be more cost-effective to use NGS-based MSI testing that is paired with a panel such as POLE and TP53 in endometrial cancer, and BRAF in colorectal cancer. It is critical that NGS-based microsatellite testing be shown to be equivalent to PCR-based MSI testing in the same tumor types. ^¶ Guidelines slightly modified from the original publication.¹⁵ Abbreviations Used: CRC: Colorectal Cancer; dMMR: Mismatch Repair Deficient; ICI: Immune Checkpoint Inhibitor; LS: Lynch Syndrome; MMR: Mismatch Repair; MMR-IHC: Mismatch Repair Immunohistochemistry; MSI: Microsatellite Instability; MSI-H: Microsatellite Instability High; MSI-L: Microsatellite Instability Low; MSS: Microsatellite Stable; NGS: Next Generation Sequencing; PCR: Polymerase Chain Reaction; pMMR: Mismatch Repair Proficient.

The Role of NGS: NGS-based assays hold promise as a single, comprehensive test for MMR status. A well-designed NGS panel can simultaneously assess thousands of microsatellite loci for instability, calculate the TMB, and sequence the coding regions of all relevant MMR genes. This integrated approach could resolve many discrepancies within a single workflow. In addition, NGS technologies, such as long-read sequencing paired with methylation detection, can simultaneously identify MLH1 promoter hypermethylation and detect large structural variants, deep intronic pathogenic variants, and promoter mutations in the MMR genes; however, significant barriers remain, including higher cost, longer turnaround times, and the critical need for cancer-type-specific validation.  

Liquid biopsy: The analysis of circulating tumor DNA (ctDNA) in a blood sample to assess MSI status is an emerging and promising noninvasive technology. Liquid biopsy could help overcome two significant sources of discordance: insufficient tissue from small biopsies and tumor heterogeneity. By sampling DNA shed from all tumor sites, ctDNA analysis may provide a more representative assessment of the overall tumor MSI status. Plasma ctDNA-based MSI assessment has been validated primarily in advanced GI malignancies; however, sensitivity varies with ctDNA shedding and can be limited in low-shedding settings (eg, localized prostate cancer and primary CNS tumors), and it may miss MSI-H subclones present at low fractional abundance in circulation.^49–52 Recent findings from the Rome Trial suggest that ctDNA-based liquid biopsies may identify patients with occasional MSI-H tumors who are missed by MMR IHC and NGS testing of the primary tumor.⁵³ Moreover, by testing patients during treatment, liquid biopsies may identify cases in which the cancer evolves from an MSS to an MSI-H phenotype⁵³; however, this technology remains under development, and its sensitivity and specificity relative to other microsatellite repair testing modalities require further validation. 

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Jeremy D. Ward, MD, PhD, FCAP, is a molecular and anatomic pathologist at Alberta Precision Laboratories and a Clinical Assistant Professor in the Department of Pathology at the University of Calgary. In his anatomic pathology role, he subspecializes in GI, liver, pancreatic, and transplant pathology. His interests include the application of genomic and proteomic methods for clinical diagnostics and predicting clinical response to targeted therapies and immune checkpoint inhibitors. He is board-certified in anatomic and clinical pathology and has recently completed a fellowship in molecular genetic pathology at Duke University. 

Matthew Hiemenz, MD, MS, FCAP, is a senior pathologist and associate medical director at Foundation Medicine. He is board-certified in anatomic and clinical pathology, molecular genetic pathology, and clinical informatics. His interests include assay validation and evidence generation for new assays and biomarkers, biomarker-driven trial design, and the molecular pathology of pediatric solid tumors. He serves on the College of American Pathologists Personalized Health Care Committee.