DNA mismatch repair protein deficient non-neoplastic colonic crypts

a novel indicator of Lynch syndrome

Rish Pai, Beth Dudley, Eve Karloski, Randall E. Brand, Neil O’Callaghan, Christophe Rosty, Daniel D. Buchanan, Mark A. Jenkins, Stephen N Thibodeau, Amy J. French, Noralane Morey Lindor, Reetesh K. Pai

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Lynch syndrome is the most common form of hereditary colorectal carcinoma. However, establishing the diagnosis of Lynch syndrome is challenging, and ancillary studies that distinguish between sporadic DNA mismatch repair (MMR) protein deficiency and Lynch syndrome are needed, particularly when germline mutation studies are inconclusive. The aim of this study was to determine if MMR protein-deficient non-neoplastic intestinal crypts can help distinguish between patients with and without Lynch syndrome. We evaluated the expression of MMR proteins in non-neoplastic intestinal mucosa obtained from colorectal surgical resection specimens from patients with Lynch syndrome-associated colorectal carcinoma (n = 52) and patients with colorectal carcinoma without evidence of Lynch syndrome (n = 70), including sporadic MMR protein-deficient colorectal carcinoma (n = 30), MMR protein proficient colorectal carcinoma (n = 30), and “Lynch-like” syndrome (n = 10). MMR protein-deficient non-neoplastic colonic crypts were identified in 19 of 122 (16%) patients. MMR protein-deficient colonic crypts were identified in 18 of 52 (35%) patients with Lynch syndrome compared to only 1 of 70 (1%) patients without Lynch syndrome (p < 0.001). This one patient had “Lynch-like” syndrome and harbored two MSH2-deficient non-neoplastic colonic crypts. MMR protein-deficient non-neoplastic colonic crypts were not identified in patients with sporadic MMR protein-deficient or MMR protein proficient colorectal carcinoma. Our findings suggest that MMR protein-deficient colonic crypts are a novel indicator of Lynch syndrome, and evaluation for MMR protein-deficient crypts may be a helpful addition to Lynch syndrome diagnostics.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalModern Pathology
DOIs
StateAccepted/In press - Jun 8 2018

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Hereditary Nonpolyposis Colorectal Neoplasms
DNA Mismatch Repair
Colorectal Neoplasms
Proteins
Protein Deficiency
Germ-Line Mutation
Intestinal Mucosa

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Pai, R., Dudley, B., Karloski, E., Brand, R. E., O’Callaghan, N., Rosty, C., ... Pai, R. K. (Accepted/In press). DNA mismatch repair protein deficient non-neoplastic colonic crypts: a novel indicator of Lynch syndrome. Modern Pathology, 1-11. https://doi.org/10.1038/s41379-018-0079-6

DNA mismatch repair protein deficient non-neoplastic colonic crypts : a novel indicator of Lynch syndrome. / Pai, Rish; Dudley, Beth; Karloski, Eve; Brand, Randall E.; O’Callaghan, Neil; Rosty, Christophe; Buchanan, Daniel D.; Jenkins, Mark A.; Thibodeau, Stephen N; French, Amy J.; Lindor, Noralane Morey; Pai, Reetesh K.

In: Modern Pathology, 08.06.2018, p. 1-11.

Research output: Contribution to journalArticle

Pai, R, Dudley, B, Karloski, E, Brand, RE, O’Callaghan, N, Rosty, C, Buchanan, DD, Jenkins, MA, Thibodeau, SN, French, AJ, Lindor, NM & Pai, RK 2018, 'DNA mismatch repair protein deficient non-neoplastic colonic crypts: a novel indicator of Lynch syndrome', Modern Pathology, pp. 1-11. https://doi.org/10.1038/s41379-018-0079-6
Pai, Rish ; Dudley, Beth ; Karloski, Eve ; Brand, Randall E. ; O’Callaghan, Neil ; Rosty, Christophe ; Buchanan, Daniel D. ; Jenkins, Mark A. ; Thibodeau, Stephen N ; French, Amy J. ; Lindor, Noralane Morey ; Pai, Reetesh K. / DNA mismatch repair protein deficient non-neoplastic colonic crypts : a novel indicator of Lynch syndrome. In: Modern Pathology. 2018 ; pp. 1-11.
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abstract = "Lynch syndrome is the most common form of hereditary colorectal carcinoma. However, establishing the diagnosis of Lynch syndrome is challenging, and ancillary studies that distinguish between sporadic DNA mismatch repair (MMR) protein deficiency and Lynch syndrome are needed, particularly when germline mutation studies are inconclusive. The aim of this study was to determine if MMR protein-deficient non-neoplastic intestinal crypts can help distinguish between patients with and without Lynch syndrome. We evaluated the expression of MMR proteins in non-neoplastic intestinal mucosa obtained from colorectal surgical resection specimens from patients with Lynch syndrome-associated colorectal carcinoma (n = 52) and patients with colorectal carcinoma without evidence of Lynch syndrome (n = 70), including sporadic MMR protein-deficient colorectal carcinoma (n = 30), MMR protein proficient colorectal carcinoma (n = 30), and “Lynch-like” syndrome (n = 10). MMR protein-deficient non-neoplastic colonic crypts were identified in 19 of 122 (16{\%}) patients. MMR protein-deficient colonic crypts were identified in 18 of 52 (35{\%}) patients with Lynch syndrome compared to only 1 of 70 (1{\%}) patients without Lynch syndrome (p < 0.001). This one patient had “Lynch-like” syndrome and harbored two MSH2-deficient non-neoplastic colonic crypts. MMR protein-deficient non-neoplastic colonic crypts were not identified in patients with sporadic MMR protein-deficient or MMR protein proficient colorectal carcinoma. Our findings suggest that MMR protein-deficient colonic crypts are a novel indicator of Lynch syndrome, and evaluation for MMR protein-deficient crypts may be a helpful addition to Lynch syndrome diagnostics.",
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