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

All causes 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

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 1:5
Breast 43,068 1:8
Colon/rectum 28,434 28,942 1:16
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

Colon/rectum 133,500 (10%) 57,100 (9%)

Pancreas 26,300 (2%) 27,800 (5%)

Stomach 22,800 (2%) 14,000 (3%)

Small intestine 4,600 1,140

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

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

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

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

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

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)