Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer.
OBJECTIVE
The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis.


METHODS
We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Germline DNA was screened for hMLH1, hMSH2, hMSH6, and hPMS2 mutations for the following patients: all from families fulfilling the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer (HNPCC); all with tumors that were high MSI, low MSI, or that lacked expression of any MMR protein; and a random sample of 23 with MS-stable tumors expressing all MMR proteins.


RESULTS
Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%.


CONCLUSIONS
Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation-carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.
Southey
Melissa C
MC
Genetic Epidemiology Laboratory, Department of Pathology, Australia.
Jenkins
Mark A
MA
Mead
Leeanne
L
Whitty
Jonathan
J
Trivett
Melanie
M
Tesoriero
Andrea A
AA
Smith
Letitia D
LD
Jennings
Kim
K
Grubb
Garry
G
Royce
Simon G
SG
Walsh
Michael D
MD
Barker
Melissa A
MA
Young
Joanne P
JP
Jass
Jeremy R
JR
St John
D James B
DJ
Macrae
Finlay A
FA
Giles
Graham G
GG
Hopper
John L
JL
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D017668:Age of Onset; D020137:Base Pair Mismatch; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D015995:Prevalence; D018570:Risk Assessment; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D012680:Sensitivity and Specificity
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C098790:MSH6 protein, S cerevisiae; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes