SATB2 and CDX2 are prognostic biomarkers in DNA mismatch repair protein deficient colon cancer

• Published in: Modern pathology Vol. 32; no. 8; pp. 1217 - 1231
• Main Authors: Ma, Changqing, Olevian, Dane, Miller, Caitlyn, Herbst, Cameron, Jayachandran, Priya, Kozak, Margaret M., Chang, Daniel T., Pai, Reetesh K.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-08-2019; Elsevier Limited
• Subjects: 13/51; 631/67/1504; 692/53/2422; Adenocarcinoma; Adenocarcinoma - chemistry; Adenocarcinoma - genetics; Adenocarcinoma - mortality; Adenocarcinoma - surgery; Adult; Aged; Aged, 80 and over; Biomarkers; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; California; CDX2 protein; CDX2 Transcription Factor - analysis; Cell differentiation; Colon cancer; Colonic Neoplasms - chemistry; Colonic Neoplasms - genetics; Colonic Neoplasms - mortality; Colonic Neoplasms - surgery; Colorectal cancer; Deoxyribonucleic acid; Disease Progression; Disease-Free Survival; DNA; DNA microarrays; DNA Mismatch Repair; DNA repair; Female; Humans; Immunohistochemistry; Laboratory Medicine; Male; Matrix Attachment Region Binding Proteins - analysis; Medicine; Medicine & Public Health; Middle Aged; Mismatch repair; Mutation; Neoplasm Staging; Pathology; Pennsylvania; Predictive Value of Tests; Progression-Free Survival; Proteins; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras) - genetics; Risk Assessment; Risk Factors; Tissue Array Analysis; Transcription Factors - analysis; Tumors; Yeast; Young Adult; California; Pennsylvania
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/s41379-019-0265-1

DNA mismatch repair protein deficient colon cancer frequently displays reduced CDX2 expression, and recent literature has suggested that negative CDX2 expression is a poor prognostic biomarker in colon cancer. We have recently demonstrated that SATB2 is an immunohistochemical marker that is complementary to CDX2. Using a tissue microarray approach, we evaluated SATB2 and CDX2 immunohistochemical expression in 514 patients with colonic adenocarcinoma including 146 with mismatch repair protein deficient tumors and correlated expression with histopathologic variables, molecular alterations, and survival. Overall, SATB2-negative and/or CDX2-negative expression was identified in 33% of mismatch repair protein deficient tumors compared with only 15% of mismatch repair protein proficient tumors (
p
 < 0.001) and in 36% of
BRAF
V600E mutated compared with only 13% of
BRAF
wild-type tumors (
p
 < 0.001). Both SATB2-negative and CDX2-negative colonic adenocarcinomas more often displayed lymphatic invasion, venous invasion, and perineural invasion (all with
p
 < 0.05). SATB2-negative expression was also more frequently identified in tumors with mucinous or signet ring cell differentiation (
p
 < 0.01 for both). In a multivariable analysis of survival in patients with mismatch repair protein deficient tumors (
n
 = 131), only tumor stage (
p

=
 0.01) and SATB2-negative and/or CDX2-negative expression (
p
 = 0.009) independently predicted disease-specific survival. Of the 99 patients with stage II or III mismatch repair protein deficient tumors, death from disease only occurred in patients with either SATB2-negative or CDX2-negative tumors, and no patients with SATB2-positive/CDX2-positive tumors developed recurrence or died of disease. SATB2 and CDX2 expression had no effect on patient survival in mismatch repair protein proficient,
BRAF
-mutated, or
KRAS
-mutated tumors. In summary, our results suggest that SATB2 and CDX2 are prognostic biomarkers in patients with mismatch repair protein deficient colon cancer and that inclusion of SATB2 and CDX2 immunohistochemistry may be helpful as part of a comprehensive pathologic risk assessment in mismatch repair protein deficient colon cancer.