Download GI Tumor Markers

Soluble chemical markers of
gastrointestinal and pancreatic
tumors
Roger L. Bertholf, Ph.D.
Associate Professor of Pathology
University of Florida Health Science Center/Jacksonville
Leading causes of death in the United States
Total Deaths
Deaths per 100,000
2,312,203
880
Cardiovascular disease
738,781
281
Cancer
537,969
205
Cerebrovascular
158,061
60
COPD
104,756
40
Accidents
89,703
34
All causes
Source: http://www.cdc.gov (1995 data)
Causes of cancer deaths in the United States
Site
Males
Females
Lifetime risk
Lung
91,405
54,538
1:12 to 1:19
Prostate
34,240
Breast
1:5
43,068
1:8
1:16
Colon/rectum
28,434
28,942
Pancreas
12,672
13,399
Source: CA Cancer J Clin 46:1996
Incidence and mortality of GI/pancreatic
tumors (1996 estimates)
Site
New Cases
Deaths
133,500 (10%)
57,100 (9%)
Pancreas
26,300 (2%)
27,800 (5%)
Stomach
22,800 (2%)
14,000 (3%)
4,600
1,140
Colon/rectum
Small intestine
Source: CA Cancer J Clin 46:1996
Colorectal cancer
• Vast majority of cases are adenocarcinomas
• Begins with adenomatous polyps
• Molecular biology
– Point mutations in ras proto-oncogene on chromosome 12
– p53 deletion (chromosome 17)
– “DCC” gene deletion (chromosome 18)
– “MCC” gene mutation (chromosome 5)
– “APC” gene mutation (chromosome 5)
Chemical markers of colorectal cancer
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Carcinoembryonic antigen (CEA)
High molecular weight alkaline phosphatase
Mucin CA M43
K-ras mutation
Carcinoembryonic antigen
• Oncofetal antigen expressed in gut, pancreas, and liver
– MW 150-300 kD; 50% carbohydrate
– Normally, production disappears after birth
• Elevated in 60-90% of colorectal cancers
– False elevations due to cirrhosis, emphysema, colitis
– Most useful for clinical staging, detecting recurrence
Chemical markers of colorectal cancer
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Carcinoembryonic antigen (CEA)
High molecular weight alkaline phosphatase
Mucin CA M43
K-ras mutation
High molecular weight alkaline phosphatase
• Also called the “fast liver” fraction
• Is more sensitive for cholestasis than liver ALP
• In patients with histologically-verified colorectal cancers:
– Sensitivity = 63%
– Specificity = 89%
• In conjunction with CEA
– Sensitivity = 72%
– Specificity = 87%
Chemical markers of colorectal cancer
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Carcinoembryonic antigen (CEA)
High molecular weight alkaline phosphatase
Mucin CA M43
K-ras mutation
CA M43
• Mucin antigen
• Using a two-site solid phase immunoassay:
– Sensitivity = 42%
– Specificity = 97%
– Positive predictive value = 98%
• In combination with CEA, sensitivity is slightly improved
Chemical markers of colorectal cancer
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Carcinoembryonic antigen (CEA)
High molecular weight alkaline phosphatase
Mucin CA M43
K-ras mutation
K-ras mutation
• Point mutations in the ras family of oncogenes have been
described in several malignancies
– K-ras mutations at codons 12 and 13
– Most common mutation is Gly-12 to Val-12
– Found in 39-47% of colorectal tumors
• Method improvements
– Competitive allele-specific oligonucleotide hybridization
– Mutant-enriched PCR
Pancreatic cancer
• 90% are exocrine, most commonly in the head of the organ
• 75% of ductal adenocarcinomas secrete mucin
• Clinically silent until it reaches advanced stage
– Lung, liver metastases
– One-year survival is 8-10%
– Five-year survival is 2%
Chemical markers of pancreatic cancer
• CA 19-9
• TPS
• CAM 17.1
CA 19-9
• Sialylated Lexa
• Secreted by gastric, colonic, endometrial, and salivary
epithelia
• Lea-b- individuals (5%) do not make Ca 19-9
• Clinical performance
– Sensitivity = 80%
– Specificity = 60-100% (depending on control group)
• Low positive predictive value in a screening scenario
Chemical markers of pancreatic cancer
• CA 19-9
• TPS
• CAM 17.1
TPS
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Specific epitope of tissue polypeptide antigen (TPA)
Nonspecific marker of cellular proliferation
Sensitivity is nearly 100% for detecting pancreatic cancer
Specificity, as expected, is low
Chemical markers of pancreatic cancer
• CA 19-9
• TPS
• CAM 17.1
CAM 17.1
• Immunoglobulin M antibody with high specificity for
intestinal mucus
• Epitope is a sialylated blood group antigen (probably I)
• Sensitivity = 67% in patients with diagnosed pancreatic
cancer (correlated with stage)
• Specificity
– 100% in healthy volunteers
– 80% in gastric cancer patients
Stomach cancer
• At one time, the most common cause of cancer death in men
– Death rate in U.S. has dropped nearly 80% since 1930
– Reason for decline is unknown
• 95% are adenocarcinoma originating in mucous cells
• Most are discovered after penetrating into the muscularis
– Metastases are common
– 20% ten-year survival if advanced
– “Early gastric cancer” (confined to mucosa or submucosa)
“He uses statistics as a drunken man uses lamp
posts -- for support rather than illumination.”
Andrew Lang (1844-1912)