Microsatellite instability and DNA mismatch repair protein deficiency in lynch syndrome colorectal polyps

Matthew B. Yurgelun, Ajay Goel, Jason L. Hornick, Ananda Sen, Danielle Kim Turgeon, Mack T. Ruffin IV, Norman E. Marcon, John A. Baron, Robert S. Bresalier, Sapna Syngal, Dean E. Brenner, C. Richard Boland, Elena M. Stoffel

Research output: Contribution to journalArticle

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Abstract

Colorectal cancers associated with Lynch syndrome are characterized by deficient DNA mismatch repair (MMR) function. Our aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR protein expression in Lynch syndrome-associated polyps. Sixty-two colorectal polyps - 37 adenomatous polyps, 23 hyperplastic polyps, and 2 sessile serrated polyps (SSP) - from34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 proteins by immunohistochemistry. High-level MSI (MSI-H) was seen in 15 of 37 (41%) adenomatous polyps, one of 23 (4%) hyperplastic polyps, and one of two (50%) SSPs. Loss of MMR protein expression was seen in 18 of 36 (50%) adenomatous polyps, zero of 21 hyperplastic polyps, and zero of two SSPs. Adenomatous polyps 8 mm or larger in size were significantly more likely to show MSI-H [OR, 9.98; 95% confidence interval (CI), 1.52-65.65; P = 0.02] and deficient MMR protein expression (OR, 3.17; 95% CI, 1.20-8.37; P = 0.02) compared with those less than 8 mm in size. All (six of six) adenomatous polyps 10 mm or larger in size showed both MSI-H and loss of MMR protein expression by immunohistochemistry. Our finding that the prevalence of MMR deficiency increases with the size of adenomatous polyps suggests that loss of MMR function is a late event in Lynch syndrome-associated colorectal neoplasia. Although testing large adenomatous polyps may be of value in the diagnostic evaluation of patients with suspected Lynch syndrome, the absence of an MMR-deficient phenotype in an adenoma cannot be considered as a strong evidence against Lynch syndrome, as it is with colorectal carcinomas.

Original languageEnglish (US)
Pages (from-to)574-582
Number of pages9
JournalCancer Prevention Research
Volume5
Issue number4
DOIs
StatePublished - Apr 1 2012

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Hereditary Nonpolyposis Colorectal Neoplasms
Protein Deficiency
Microsatellite Instability
DNA Mismatch Repair
Adenomatous Polyps
Polyps
Colorectal Neoplasms
Proteins
Immunohistochemistry
DNA Repair-Deficiency Disorders
Confidence Intervals
Turcot syndrome
Adenoma
Microsatellite Repeats
Phenotype
Polymerase Chain Reaction
Mutation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yurgelun, Matthew B. ; Goel, Ajay ; Hornick, Jason L. ; Sen, Ananda ; Turgeon, Danielle Kim ; Ruffin IV, Mack T. ; Marcon, Norman E. ; Baron, John A. ; Bresalier, Robert S. ; Syngal, Sapna ; Brenner, Dean E. ; Boland, C. Richard ; Stoffel, Elena M. / Microsatellite instability and DNA mismatch repair protein deficiency in lynch syndrome colorectal polyps. In: Cancer Prevention Research. 2012 ; Vol. 5, No. 4. pp. 574-582.
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abstract = "Colorectal cancers associated with Lynch syndrome are characterized by deficient DNA mismatch repair (MMR) function. Our aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR protein expression in Lynch syndrome-associated polyps. Sixty-two colorectal polyps - 37 adenomatous polyps, 23 hyperplastic polyps, and 2 sessile serrated polyps (SSP) - from34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 proteins by immunohistochemistry. High-level MSI (MSI-H) was seen in 15 of 37 (41{\%}) adenomatous polyps, one of 23 (4{\%}) hyperplastic polyps, and one of two (50{\%}) SSPs. Loss of MMR protein expression was seen in 18 of 36 (50{\%}) adenomatous polyps, zero of 21 hyperplastic polyps, and zero of two SSPs. Adenomatous polyps 8 mm or larger in size were significantly more likely to show MSI-H [OR, 9.98; 95{\%} confidence interval (CI), 1.52-65.65; P = 0.02] and deficient MMR protein expression (OR, 3.17; 95{\%} CI, 1.20-8.37; P = 0.02) compared with those less than 8 mm in size. All (six of six) adenomatous polyps 10 mm or larger in size showed both MSI-H and loss of MMR protein expression by immunohistochemistry. Our finding that the prevalence of MMR deficiency increases with the size of adenomatous polyps suggests that loss of MMR function is a late event in Lynch syndrome-associated colorectal neoplasia. Although testing large adenomatous polyps may be of value in the diagnostic evaluation of patients with suspected Lynch syndrome, the absence of an MMR-deficient phenotype in an adenoma cannot be considered as a strong evidence against Lynch syndrome, as it is with colorectal carcinomas.",
author = "Yurgelun, {Matthew B.} and Ajay Goel and Hornick, {Jason L.} and Ananda Sen and Turgeon, {Danielle Kim} and {Ruffin IV}, {Mack T.} and Marcon, {Norman E.} and Baron, {John A.} and Bresalier, {Robert S.} and Sapna Syngal and Brenner, {Dean E.} and Boland, {C. Richard} and Stoffel, {Elena M.}",
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Yurgelun, MB, Goel, A, Hornick, JL, Sen, A, Turgeon, DK, Ruffin IV, MT, Marcon, NE, Baron, JA, Bresalier, RS, Syngal, S, Brenner, DE, Boland, CR & Stoffel, EM 2012, 'Microsatellite instability and DNA mismatch repair protein deficiency in lynch syndrome colorectal polyps', Cancer Prevention Research, vol. 5, no. 4, pp. 574-582. https://doi.org/10.1158/1940-6207.CAPR-11-0519

Microsatellite instability and DNA mismatch repair protein deficiency in lynch syndrome colorectal polyps. / Yurgelun, Matthew B.; Goel, Ajay; Hornick, Jason L.; Sen, Ananda; Turgeon, Danielle Kim; Ruffin IV, Mack T.; Marcon, Norman E.; Baron, John A.; Bresalier, Robert S.; Syngal, Sapna; Brenner, Dean E.; Boland, C. Richard; Stoffel, Elena M.

In: Cancer Prevention Research, Vol. 5, No. 4, 01.04.2012, p. 574-582.

Research output: Contribution to journalArticle

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AU - Yurgelun, Matthew B.

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AU - Hornick, Jason L.

AU - Sen, Ananda

AU - Turgeon, Danielle Kim

AU - Ruffin IV, Mack T.

AU - Marcon, Norman E.

AU - Baron, John A.

AU - Bresalier, Robert S.

AU - Syngal, Sapna

AU - Brenner, Dean E.

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AU - Stoffel, Elena M.

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N2 - Colorectal cancers associated with Lynch syndrome are characterized by deficient DNA mismatch repair (MMR) function. Our aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR protein expression in Lynch syndrome-associated polyps. Sixty-two colorectal polyps - 37 adenomatous polyps, 23 hyperplastic polyps, and 2 sessile serrated polyps (SSP) - from34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 proteins by immunohistochemistry. High-level MSI (MSI-H) was seen in 15 of 37 (41%) adenomatous polyps, one of 23 (4%) hyperplastic polyps, and one of two (50%) SSPs. Loss of MMR protein expression was seen in 18 of 36 (50%) adenomatous polyps, zero of 21 hyperplastic polyps, and zero of two SSPs. Adenomatous polyps 8 mm or larger in size were significantly more likely to show MSI-H [OR, 9.98; 95% confidence interval (CI), 1.52-65.65; P = 0.02] and deficient MMR protein expression (OR, 3.17; 95% CI, 1.20-8.37; P = 0.02) compared with those less than 8 mm in size. All (six of six) adenomatous polyps 10 mm or larger in size showed both MSI-H and loss of MMR protein expression by immunohistochemistry. Our finding that the prevalence of MMR deficiency increases with the size of adenomatous polyps suggests that loss of MMR function is a late event in Lynch syndrome-associated colorectal neoplasia. Although testing large adenomatous polyps may be of value in the diagnostic evaluation of patients with suspected Lynch syndrome, the absence of an MMR-deficient phenotype in an adenoma cannot be considered as a strong evidence against Lynch syndrome, as it is with colorectal carcinomas.

AB - Colorectal cancers associated with Lynch syndrome are characterized by deficient DNA mismatch repair (MMR) function. Our aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR protein expression in Lynch syndrome-associated polyps. Sixty-two colorectal polyps - 37 adenomatous polyps, 23 hyperplastic polyps, and 2 sessile serrated polyps (SSP) - from34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 proteins by immunohistochemistry. High-level MSI (MSI-H) was seen in 15 of 37 (41%) adenomatous polyps, one of 23 (4%) hyperplastic polyps, and one of two (50%) SSPs. Loss of MMR protein expression was seen in 18 of 36 (50%) adenomatous polyps, zero of 21 hyperplastic polyps, and zero of two SSPs. Adenomatous polyps 8 mm or larger in size were significantly more likely to show MSI-H [OR, 9.98; 95% confidence interval (CI), 1.52-65.65; P = 0.02] and deficient MMR protein expression (OR, 3.17; 95% CI, 1.20-8.37; P = 0.02) compared with those less than 8 mm in size. All (six of six) adenomatous polyps 10 mm or larger in size showed both MSI-H and loss of MMR protein expression by immunohistochemistry. Our finding that the prevalence of MMR deficiency increases with the size of adenomatous polyps suggests that loss of MMR function is a late event in Lynch syndrome-associated colorectal neoplasia. Although testing large adenomatous polyps may be of value in the diagnostic evaluation of patients with suspected Lynch syndrome, the absence of an MMR-deficient phenotype in an adenoma cannot be considered as a strong evidence against Lynch syndrome, as it is with colorectal carcinomas.

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