<i>HSP110</i>T17 simplifies and improves the microsatellite instability testing in patients with colorectal cancer

Buhard, Olivier; Lagrange, Anaïs; Guilloux, Agathe; Colas, Chrystelle; Chouchène, Mouna; Wanherdrick, Kristell; Coulet, Florence; Guillerm, Erell; Dorard, Coralie; Marisa, Laëtitia; Bokhari, A'dem; Greene, Malorie; El-Murr, Nizar; Bodo, Sahra; Muleris, Martine; Sourouille, Isabelle; Svrcek, Magali; Cervera, Pascale; Blanché, Hélène; Lefèvre, Jérémie H.; Parc, Yann; Lepage, Côme; Chapusot, Caroline; Bouvier, Anne–Marie; Gaub, Marie–Pierre; Sèlves, Janick; Garrett, Kerryn L.; Iacopetta, Barry; Soong, Richie; Hamelin, Richard; Garrido, Carmen; Lascols, Olivier; André, Thierry; Fléjou, Jean‐François; Collura, Ada; Duval, Alex

doi:10.1136/jmedgenet-2015-103518

Cited by 50 publications

(41 citation statements)

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“…showed better sensitivity compared with the pentaplex panel [0.984 (95% CI 0.968 to 0.995) versus 0.951 (95% CI 0.925 to 0.972)] and similar specificity [0.997 (95% CI 0.989 to 1.000) for both) for the detection of MSI. Thus, HT17 DNA repeat seems to constitute a superior marker for the diagnosis of MSI phenotype in patients with CRC compared with the standard pentaplex panel [9].…”

Section: Polymerase Chain Reactionmentioning

confidence: 98%

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Immunotherapy and patients treated for cancer with microsatellite instability

et al. 2017

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Microsatellite instability (MSI) is a tumor phenotype linked to somatic or germline (Lynch syndrome) inactivating alterations of DNA mismatch repair genes. A broad spectrum of neoplasms exhibits MSI phenotype, mainly colorectal cancer, endometrial cancer, and gastric cancer. MSI tumors are characterized by dense immune infiltration and high load of tumor neo-antigens. Growing evidence is accumulating on the efficacy of immune checkpoint inhibition for patients treated for MSI solid tumors. We present a comprehensive overview of MSI phenotype, its biological landscape and current diagnostic methods. Then we focus on MSI as a predictive biomarker of response to immune checkpoint inhibition in the context of colorectal cancer and non-colorectal tumors.

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Section: Polymerase Chain Reactionmentioning

confidence: 98%

“…MMR deficiency is not a direct transforming event. Most oncogenic alterations found in MMRdeficient (dMMR) tumors are somatic mutation events that occur as a result of MSI [7][8][9]. The MSI process is expected to be oncogenic when it affects DNA repeat sequences that have a functional role.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy and patients treated for cancer with microsatellite instability

et al. 2017

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“…We used the mononucleotide repeat microsatellite marker HSP110 T17 (Buhard et al., ; Collura et al., ; Dorard et al., ) to develop an E‐ ice ‐COLD‐PCR assay for MSI detection in CRC. The natural polymorphism of this microsatellite marker has previously been evaluated in 1,037 individuals from 54 worldwide populations of the Human Genome Diversity Panel (Cann et al., ) and revealed the presence of only two alleles: T16 (27.7%) and T17 (72.3%) (Buhard et al., ). Another common allele: T15 (rs545157484), with a global MAF of 0.1359, was also identified based on whole genome sequencing data from the 1000 Genomes Project (Auton et al., ).…”

Section: Resultsmentioning

confidence: 99%

“…The somatic mutation of this marker, found in the great majority of MSI CRCs and in more than 50% of MSI adenomas, carries prognostic and predictive information for the response to chemotherapy (5‐FU and oxaliplatin) (Collura et al., ; Dorard et al., ). HSP110 T17 has been shown to constitute an improved biomarker for the diagnosis of MSI in CRC, including LS, as it displays a higher sensitivity (98.4%) than the pentaplex panel, and is simpler to use as only one marker needs to be analyzed (Buhard et al., ).…”

Section: Introductionmentioning

confidence: 99%

“…In the present study, we hypothesized that E‐ ice ‐COLD‐PCR is suitable for improving the detection of MSI in DNA when using a highly monomorphic DNA repeat sequence, which otherwise shows a very high mutation rate in MMR deficient tumor samples, e.g., the HSP110 T17 (HT17) (Buhard et al., ). We then developed, for the first time, E‐ ice ‐COLD‐PCR using HT17, which can present a loss of 1–9 T nucleotides in CRCs with MSI.…”

Section: Introductionmentioning

confidence: 99%

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Major improvement in the detection of microsatellite instability in colorectal cancer using HSP110 T17 E-ice -COLD-PCR

et al. 2017

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Every colorectal cancer (CRC) patient should be tested for microsatellite instability (MSI) to screen for Lynch syndrome. Evaluation of MSI status involves screening tumor DNA for the presence of somatic deletions in DNA repeats using PCR followed by fragment analysis. While this method may lack sensitivity due to the presence of a high level of germline DNA, which frequently contaminates the core of primary colon tumors, no other method developed to date is capable of modifying the standard PCR protocol to achieve improvement of MSI detection. Here, we describe a new approach developed for the ultra-sensitive detection of MSI in CRC based on E-ice-COLD-PCR, using HSP110 T17, a mononucleotide DNA repeat previously proposed as an optimal marker to detect MSI in tumor DNA, and an oligo(dT) LNA blocker probe complementary to wild-type genotypes. The HT17 E-ice-COLD-PCR assay improved MSI detection by 20-200-fold compared with standard PCR using HT17 alone. It presents an analytical sensitivity of 0.1%-0.05% of mutant alleles in wild-type background, thus greatly improving MSI detection in CRC samples highly contaminated with normal DNA. HT17 E-ice-COLD-PCR is a rapid, cost-effective, easy-to-implement, and highly sensitive method, which could significantly improve the detection of MSI in routine clinical testing.

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Association of Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer With Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status

et al. 2019

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Primary resistance to immune checkpoint inhibitors is observed in 10% to 40% of patients with metastatic colorectal cancer (mCRC) displaying microsatellite instability (MSI) or defective mismatch repair (dMMR). OBJECTIVE To investigate possible mechanisms underlying primary resistance to immune checkpoint inhibitors of mCRC displaying MSI or dMMR. DESIGN, SETTING, AND PARTICIPANTS This post hoc analysis of a single-center, prospective cohort included 38 patients with mCRC diagnosed as MSI or dMMR by local laboratories and entered into trials of immune checkpoint inhibitors between January 1, 2015, and December 31, 2016. The accuracy of MSI or dMMR status was also assessed in a retrospective cohort comprising 93 cases of mCRC that were diagnosed as MSI or dMMR between January 1, 1998, and December 31, 2016, in 6 French hospitals. Primary resistance of mCRC was defined as progressive disease according to Response Evaluation Criteria in Solid Tumors criteria, 6 to 8 weeks after initiation of immune checkpoint inhibitors, without pseudo-progression. All tumor samples were reassessed for dMMR status using immunohistochemistry with antibodies directed against MLH1, MSH2, MSH6, and PMS2, and for MSI using polymerase chain reaction with pentaplex markers and with the HSP110 T17 (HT17) repeat. MAIN OUTCOMES AND MEASURES The primary outcome was positive predictive value. RESULTS Among the 38 patients (15 women and 23 men; mean [SD] age, 55.6 [13.7] years) in the study with mCRC displaying MSI or dMMR, primary resistance to immune checkpoint inhibitors was observed in 5 individuals (13%). Reassessment of the status of MSI or dMMR revealed that 3 (60%) of these 5 resistant tumors were microsatellite stable or displayed proficient mismatch repair. The positive predictive value of MSI or dMMR status assessed by local laboratories was therefore 92.1% (95% CI, 78.5%-98.0%). In the retrospective cohort of 93 patients (44 women and 49 men; mean [SD] age, 56.8 [18.3] years) without immune checkpoint inhibitor treatment, misdiagnosis of the MSI or dMMR status by local assessment was 10% (n = 9), with a positive predictive value of 90.3% (95% CI, 82.4%-95.0%). Testing for MSI with the HT17 assay confirmed the MSI or dMMR status in 2 of 4 cases showing discrepant results between immunohistochemistry and pentaplex polymerase chain reaction (ie, dMMR but microsatellite stable). CONCLUSIONS AND RELEVANCE Primary resistance of mCRC displaying MSI or dMMR to immune checkpoint inhibitors is due mainly to misdiagnosis of their MSI or dMMR status. Larger studies are required to confirm these findings. Microsatellite instability or dMMR status should be tested routinely using both immunohistochemistry and polymerase chain reaction methods prior to treatment with immune checkpoint inhibitors.

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HSP110T17 simplifies and improves the microsatellite instability testing in patients with colorectal cancer

Abstract: HT17 simplifies and improves the current standard molecular methods for detecting MSI in CRC.

Cited by 50 publications

References 24 publications

Immunotherapy and patients treated for cancer with microsatellite instability

Immunotherapy and patients treated for cancer with microsatellite instability

Major improvement in the detection of microsatellite instability in colorectal cancer using HSP110 T17 E-ice -COLD-PCR

Association of Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer With Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status

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