Functional repair assay for the diagnosis of constitutional mismatch repair deficiency from non-neoplastic tissue

Andrew Y. Shuen, Stella Lanni, Gagan B. Panigrahi, Melissa Edwards, Lisa Yu, Brittany B. Campbell, Ariane Mandel, Cindy Zhang, Nataliya Zhukova, Musa Alharbi, Mark Bernstein, Daniel C Bowers, Sara Carroll, Kristina A. Cole, Shlomi Constantini, Bruce Crooks, Rina Dvir, Roula Farah, Nobuko Hijiya, Ben GeorgeTheodore W Laetsch, Valerie Larouche, Scott Lindhorst, Rebecca C. Luiten, Vanan Magimairajan, Gary Mason, Warren Mason, Oz Mordechai, Naureen Mushtaq, Garth Nicholas, Michael Oren, Laura Palma, Luis Alberto Pedroza, Jagadeesh Ramdas, David Samuel, Kami Wolfe Schneider, Andrea Seeley, Kara Semotiuk, Ashraf Shamvil, David Sumerauer, Helen Toledano, Patrick Tomboc, Margaret Wierman, An Van Damme, Yi Yen Lee, Michal Zapotocky, Eric Bouffet, Carol Durno, Melyssa Aronson, Steve Gallinger, William D. Foulkes, David Malkin, Uri Tabori, Christopher E. Pearson

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

PURPOSE Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS In vitro MMR activity was quantified using a 39-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus–transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 6 1.56%) relative to controls (n = 6; mean, 44.00 6 8.65%; P, .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

Original languageEnglish (US)
Pages (from-to)461-470
Number of pages10
JournalJournal of Clinical Oncology
Volume37
Issue number6
DOIs
StatePublished - Jan 1 2019

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DNA Mismatch Repair
Li-Fraumeni Syndrome
Hereditary Nonpolyposis Colorectal Neoplasms
Neurofibromatosis 1
Cell Line
Neoplasms
Pseudogenes
Turcot syndrome
Early Detection of Cancer
Lymphocytes
Sensitivity and Specificity
Mutation
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Shuen, A. Y., Lanni, S., Panigrahi, G. B., Edwards, M., Yu, L., Campbell, B. B., ... Pearson, C. E. (2019). Functional repair assay for the diagnosis of constitutional mismatch repair deficiency from non-neoplastic tissue. Journal of Clinical Oncology, 37(6), 461-470. https://doi.org/10.1200/JCO.18.00474

Functional repair assay for the diagnosis of constitutional mismatch repair deficiency from non-neoplastic tissue. / Shuen, Andrew Y.; Lanni, Stella; Panigrahi, Gagan B.; Edwards, Melissa; Yu, Lisa; Campbell, Brittany B.; Mandel, Ariane; Zhang, Cindy; Zhukova, Nataliya; Alharbi, Musa; Bernstein, Mark; Bowers, Daniel C; Carroll, Sara; Cole, Kristina A.; Constantini, Shlomi; Crooks, Bruce; Dvir, Rina; Farah, Roula; Hijiya, Nobuko; George, Ben; Laetsch, Theodore W; Larouche, Valerie; Lindhorst, Scott; Luiten, Rebecca C.; Magimairajan, Vanan; Mason, Gary; Mason, Warren; Mordechai, Oz; Mushtaq, Naureen; Nicholas, Garth; Oren, Michael; Palma, Laura; Pedroza, Luis Alberto; Ramdas, Jagadeesh; Samuel, David; Schneider, Kami Wolfe; Seeley, Andrea; Semotiuk, Kara; Shamvil, Ashraf; Sumerauer, David; Toledano, Helen; Tomboc, Patrick; Wierman, Margaret; Damme, An Van; Lee, Yi Yen; Zapotocky, Michal; Bouffet, Eric; Durno, Carol; Aronson, Melyssa; Gallinger, Steve; Foulkes, William D.; Malkin, David; Tabori, Uri; Pearson, Christopher E.

In: Journal of Clinical Oncology, Vol. 37, No. 6, 01.01.2019, p. 461-470.

Research output: Contribution to journalArticle

Shuen, AY, Lanni, S, Panigrahi, GB, Edwards, M, Yu, L, Campbell, BB, Mandel, A, Zhang, C, Zhukova, N, Alharbi, M, Bernstein, M, Bowers, DC, Carroll, S, Cole, KA, Constantini, S, Crooks, B, Dvir, R, Farah, R, Hijiya, N, George, B, Laetsch, TW, Larouche, V, Lindhorst, S, Luiten, RC, Magimairajan, V, Mason, G, Mason, W, Mordechai, O, Mushtaq, N, Nicholas, G, Oren, M, Palma, L, Pedroza, LA, Ramdas, J, Samuel, D, Schneider, KW, Seeley, A, Semotiuk, K, Shamvil, A, Sumerauer, D, Toledano, H, Tomboc, P, Wierman, M, Damme, AV, Lee, YY, Zapotocky, M, Bouffet, E, Durno, C, Aronson, M, Gallinger, S, Foulkes, WD, Malkin, D, Tabori, U & Pearson, CE 2019, 'Functional repair assay for the diagnosis of constitutional mismatch repair deficiency from non-neoplastic tissue', Journal of Clinical Oncology, vol. 37, no. 6, pp. 461-470. https://doi.org/10.1200/JCO.18.00474
Shuen, Andrew Y. ; Lanni, Stella ; Panigrahi, Gagan B. ; Edwards, Melissa ; Yu, Lisa ; Campbell, Brittany B. ; Mandel, Ariane ; Zhang, Cindy ; Zhukova, Nataliya ; Alharbi, Musa ; Bernstein, Mark ; Bowers, Daniel C ; Carroll, Sara ; Cole, Kristina A. ; Constantini, Shlomi ; Crooks, Bruce ; Dvir, Rina ; Farah, Roula ; Hijiya, Nobuko ; George, Ben ; Laetsch, Theodore W ; Larouche, Valerie ; Lindhorst, Scott ; Luiten, Rebecca C. ; Magimairajan, Vanan ; Mason, Gary ; Mason, Warren ; Mordechai, Oz ; Mushtaq, Naureen ; Nicholas, Garth ; Oren, Michael ; Palma, Laura ; Pedroza, Luis Alberto ; Ramdas, Jagadeesh ; Samuel, David ; Schneider, Kami Wolfe ; Seeley, Andrea ; Semotiuk, Kara ; Shamvil, Ashraf ; Sumerauer, David ; Toledano, Helen ; Tomboc, Patrick ; Wierman, Margaret ; Damme, An Van ; Lee, Yi Yen ; Zapotocky, Michal ; Bouffet, Eric ; Durno, Carol ; Aronson, Melyssa ; Gallinger, Steve ; Foulkes, William D. ; Malkin, David ; Tabori, Uri ; Pearson, Christopher E. / Functional repair assay for the diagnosis of constitutional mismatch repair deficiency from non-neoplastic tissue. In: Journal of Clinical Oncology. 2019 ; Vol. 37, No. 6. pp. 461-470.
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abstract = "PURPOSE Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS In vitro MMR activity was quantified using a 39-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus–transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 6 1.56{\%}) relative to controls (n = 6; mean, 44.00 6 8.65{\%}; P, .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100{\%} specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.",
author = "Shuen, {Andrew Y.} and Stella Lanni and Panigrahi, {Gagan B.} and Melissa Edwards and Lisa Yu and Campbell, {Brittany B.} and Ariane Mandel and Cindy Zhang and Nataliya Zhukova and Musa Alharbi and Mark Bernstein and Bowers, {Daniel C} and Sara Carroll and Cole, {Kristina A.} and Shlomi Constantini and Bruce Crooks and Rina Dvir and Roula Farah and Nobuko Hijiya and Ben George and Laetsch, {Theodore W} and Valerie Larouche and Scott Lindhorst and Luiten, {Rebecca C.} and Vanan Magimairajan and Gary Mason and Warren Mason and Oz Mordechai and Naureen Mushtaq and Garth Nicholas and Michael Oren and Laura Palma and Pedroza, {Luis Alberto} and Jagadeesh Ramdas and David Samuel and Schneider, {Kami Wolfe} and Andrea Seeley and Kara Semotiuk and Ashraf Shamvil and David Sumerauer and Helen Toledano and Patrick Tomboc and Margaret Wierman and Damme, {An Van} and Lee, {Yi Yen} and Michal Zapotocky and Eric Bouffet and Carol Durno and Melyssa Aronson and Steve Gallinger and Foulkes, {William D.} and David Malkin and Uri Tabori and Pearson, {Christopher E.}",
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TY - JOUR

T1 - Functional repair assay for the diagnosis of constitutional mismatch repair deficiency from non-neoplastic tissue

AU - Shuen, Andrew Y.

AU - Lanni, Stella

AU - Panigrahi, Gagan B.

AU - Edwards, Melissa

AU - Yu, Lisa

AU - Campbell, Brittany B.

AU - Mandel, Ariane

AU - Zhang, Cindy

AU - Zhukova, Nataliya

AU - Alharbi, Musa

AU - Bernstein, Mark

AU - Bowers, Daniel C

AU - Carroll, Sara

AU - Cole, Kristina A.

AU - Constantini, Shlomi

AU - Crooks, Bruce

AU - Dvir, Rina

AU - Farah, Roula

AU - Hijiya, Nobuko

AU - George, Ben

AU - Laetsch, Theodore W

AU - Larouche, Valerie

AU - Lindhorst, Scott

AU - Luiten, Rebecca C.

AU - Magimairajan, Vanan

AU - Mason, Gary

AU - Mason, Warren

AU - Mordechai, Oz

AU - Mushtaq, Naureen

AU - Nicholas, Garth

AU - Oren, Michael

AU - Palma, Laura

AU - Pedroza, Luis Alberto

AU - Ramdas, Jagadeesh

AU - Samuel, David

AU - Schneider, Kami Wolfe

AU - Seeley, Andrea

AU - Semotiuk, Kara

AU - Shamvil, Ashraf

AU - Sumerauer, David

AU - Toledano, Helen

AU - Tomboc, Patrick

AU - Wierman, Margaret

AU - Damme, An Van

AU - Lee, Yi Yen

AU - Zapotocky, Michal

AU - Bouffet, Eric

AU - Durno, Carol

AU - Aronson, Melyssa

AU - Gallinger, Steve

AU - Foulkes, William D.

AU - Malkin, David

AU - Tabori, Uri

AU - Pearson, Christopher E.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - PURPOSE Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS In vitro MMR activity was quantified using a 39-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus–transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 6 1.56%) relative to controls (n = 6; mean, 44.00 6 8.65%; P, .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

AB - PURPOSE Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS In vitro MMR activity was quantified using a 39-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus–transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 6 1.56%) relative to controls (n = 6; mean, 44.00 6 8.65%; P, .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

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