Molecular biology of pancreatic cancer

Table 1 Pancreatic cancer risk factors

Factor	Type	Group	Maximum risk to average ratio
Smoking	Exogenous	Behavioral	3
Alcohol	Exogenous	Behavioral	Non-significant
Diet/obesity	Exogenous	Behavioral	1.72
Occupational hazard	Exogenous	Environmental	-
Radiation	Exogenous	Environmental	Inconclusive
Age	Endogenous	Biological	-
Race	Endogenous	Biological/behavioral/environmental	1.4
Family history	Endogenous	Genetic	32
Peutz-Jeghers syndrome	Endogenous	Genetic	132
FAMMM syndrome	Endogenous	Genetic	13.1
HNPCC	Endogenous	Genetic	7
Hereditary pancreatitis	Endogenous	Genetic	60
Chronic pancreatitis	Endogenous	Behavioral	26.3
Diabetes mellitus	Endogenous	Biological/environmental	2.0
Hormonal	Endogenous	Biological	Inconclusive
Allergy	Endogenous	Biological	Non-significant

FAMMM: Familial atypical multiple mole melanoma; HNPCC: Hereditary non-polyposis colorectal carcinoma syndrome.

Table 2 Genes most frequently mutated in pancreatic cancer[45,46]

Gene symbols	Protein name	Mutation frequency (%)	Type	Main signaling or system
KRAS	K-ras	58	Proto-oncogene	Ras/Raf/MAPK
TP53	Tumor protein p53	37	Tumor suppressor	Apoptosis Cell cycle control
CDKN2A	Tumor protein p16 (INK4A)	29	Tumor suppressor	Cell cycle control
CTNNB1	β-catenin	24	Proto-oncogene	Wnt
SMAD4 DPC4	Smad Dpc4	22	Tumor suppressor	TNFbeta/SMAD
APC	Apc	16	Tumor suppressor	Wnt
PIK3CA	Phosphoinositide 3-kinase	5	Proto-oncogene	PTEN/PI3K/AKT

DPC: Deleted in pancreatic cancer; APC: Adenomatous polyposis coli; MAPK: Mitogen-activated protein kinase.

Table 3 Overview of hereditary syndromes predisposing to pancreatic cancer

Syndrome	Gene	Life-time risk	Relative risk
FAMMM	CDKN2A	10%-15%	20-34
HBOC	BRCA2	5%	10
HBOC	BRCA1	Not known	2
Hereditary pancreatitis	PRSS1/TRY1	30%-50%	50
Lynch syndrome	MLH1/MSH2	Not known	Not known
Peutz–Jeghers syndrome	STK11/LKB1	36%	136
FAP	APC	Not known	4
Li–Faumeni syndrome	p53	Not known	Not known
FPC	Not known	Up to 50%	18-57

APC: Adenomatous polyposis coli; FAMMM: Familial atypical multiple mole melanoma; FAP: Familial adenomatous polyposis; FPC: Familial pancreatic cancer; HBOC: Hereditary breast and ovarian syndrome. Adapted from[72].

Table 4 Overview of biomarkers in pancreatic cancer

Biomarker	Sensitivity (%)	Specificity (%)
CEA	45	75
Carcinoembryonic antigen-related cell adhesion molecule-1	85	98
Ca 19-9	80	73
SPan-1	81-94	75
DUPAN-2	48-80	75-85
Macrophage inhibitory cytokine 1	90	62
Alpha4GnT	76	83
PAM4	77	95
Pancreatic juice DNA methylation	82	100
Fecal K-ras	77	81

CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; DUPAN-2: Pancreatic cancer-associated antigen 2; PAM4: Peptidylglycine alpha-amidating monooxygenase 4.

Table 5 Level of risk according to cumulative risk factors

Factors	Risk level
Race/sex: Male; black; Ashkenazi Jewish descent. Exposures: obesity; smoking; diabetes mellitus; Helicobacter pylori infection.Family history: Cancer history in a first-degree relative; history of pancreatic cancer in one first-degree relative. Inherited conditions: Hereditary non-polyposis colorectal cancer; familial adenomatous polyposis; BRCA1 mutation carrier	Low (less than 5-fold)
Family history: History of pancreatic cancer in two first-degree relatives. Inherited conditions: cystic fibrosis; BRCA2 mutation carrier. Comorbidity: Chronic pancreatitis	Moderate (5- to 10-fold)
Inherited conditions: FAMMM kindreds with p16 germline mutation and at least one case of pancreatic cancer in a first-degree or second-degree relative; hereditary pancreatitis; Peutz–Jeghers syndrome; BRCA2 or BRCA1 mutation carrier with at least one case of pancreatic cancer in a first-degree or second-degree relative. Family history: Three or more first-degree; second-degree or third-degree relatives with pancreatic cancer	High (greater than 10-fold)

FAMMM: Familial atypical multiple mole melanoma.