Soluble chemical markers of Soluble chemical markers of gastrointestinal and pancreatic gastrointestinal and pancreatic

tumorstumors

Roger L. Bertholf, Ph.D.Roger L. Bertholf, Ph.D.Associate Professor of PathologyAssociate Professor of Pathology

University of Florida Health Science Center/JacksonvilleUniversity 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 He uses statistics as a drunken man uses lamp posts -- for support rather than illumination.”posts -- for support rather than illumination.”

Andrew Lang (1844-1912)Andrew Lang (1844-1912)