HomeSite structureContactsWeb-linksRussianEnglish

Cancer biology 
Cancer stem cells 
Growth factors & Cytokines 
Tumour angiogenesis 
Tumour invasion & metastasis 
Skin cancer 
Brain tumors 
Breast cancer 
Endocrine tumors 
Lung cancer 
Pancreatic cancer 
Colon cancer 
Prostate cancer 
Cancer complications 
Cancer therapy 

EPIDEMIOLOGY, RISK FACTORS, AND DEMOGRAPHICS

Pancreatic cancer is one of the deadliest of all of the solid malignancies. The five-year survival rate is only 4%. The American Cancer Society estimates that 37,170 Americans will be diagnosed with pancreatic cancer in the year 2007 and 33,370 will die from it, making pancreatic cancer the fourth leading cause of cancer death. In the United States, the age-adjusted incidence of pancreatic cancer is higher in blacks (14.9 cases per 100,000) than in whites (11.1 cases per 100,000), and it is higher in men (12.8 cases per 100,000) than in women (10.0 cases per 100,000) (http://seer.cancer.gov/).

A number of risk factors have been identified. Pancreatic cancer is predominantly a disease of the elderly. Pancreatic cancer is rare before the age of 40, and the median age at diagnosis is 73 years (http://seer.cancer.gov/). Cigarette smoking is by far the leading preventable cause of pancreatic cancer. Cigarette smoking doubles the riskof pancreatic cancer (Relative Risk = 2), and it is believed that as many as one in four cases of pancreatic cancer may be attributable to smoking. Other established risk factors include diets high in meats and fat, low serum folate levels, obesity, long-standing diabetes mellitus, and chronic pancreatitis. A well-publicized study linking coffee consumption with pancreatic cancer had methodological flaws, and more recent studies did not demonstrate any significant associations.

One of the more interesting risk factors for pancreatic cancer is a family history of this disease. Individuals with a strong family history of pancreatic cancer have a significantly increased risk of developing the disease themselves. For example, individuals with a first-degree relative with pancreatic cancer have a 2.3-fold increased risk of developing the malignancy. Klein et al. have shown that this risk increases with the number of first-degree relatives one has with pancreatic cancer, and that the simplest model to explain this aggregation in families is an autosomal dominant inheritance of a rare allele. As summarized in Table 1, a number of germ-line genetic alterations have been associated with an increased risk of pancreatic cancer. These germ-line genetic alterations provide insight into the pathogenesis of pancreatic cancer.

Table 1. Genes associated with an increased risk of pancreatic cancer

Individual

Gene

Relative risk

Risk by age 70

Cancer morphology

Other cancers

No history

None

1

0.5%

NS

None

Breast cancer

BRCA2

3.5–10X

5%

NS

Breast, ovary, and prostate

BRCA1

2X

1%

Breast cancer with basaloid features

Breast, ovary, and prostate

FAMMM

P16 (CDKN2A)

20–34X

10%–17%

NS

Melanoma

Familial pancreatic cancer (3 FDR)

Unknown

32X

16%

NS

Unknown

Familial pancreatitis

PRSS1

50–80X

25%–40%

Pancreatic cancers in the background of severe diffuse chronic pancreatitis

None

Peutz-Jeghers

STK11/LKB1

132X

30%–60%

NS

Gastroesophageal, small bowel, colorectal, and breast

HNPCC

hMLH1, hMSH2, others

Unknown

< 5%

Medullary and colloid phenotypes

Colorectal, endometrial, stomach, ovarian, ureter and renal pelvis, biliary tract, and brain

Young-age-onset pancreatic cancer

FANC-C and FANC-G

Unknown

Unknown

NS

Unknown

3 FDR, 3 or more first-degree relatives with pancreatic cancer; FAMMM, familial atypical multiple mole melanoma syndrome; HNPCC, hereditary nonpolyposis colorectal cancer syndrome; NS, nonspecific.

Several features of the genetic syndromes associated with the familial clustering of pancreatic cancer deserve special note. First, the penetrance of cancer in the gene carriers is incomplete. For example, some individuals with germ-line BRCA2 gene mutations do not have a strong family history of cancer. Goggins et al. studied a series of 41 apparently sporadic pancreatic cancer patients and four (9.8%) of the 41 patients harbored a germ-line BRCA2 gene mutation. Only one of the four had a family history of breast cancer and none had a family history of pancreatic cancer. Clearly, the absence of a strong family history of cancer cannot be used to rule out a germ-line mutation.

Second, individuals can be identified, tested for one of these mutations, and counseled on their pancreatic cancer risk. For example, the Peutz-Jeghers syndrome is characterized by melanocytic macules on the lips and buccal mucosa, and hamartomatous polyps of the gastrointestinal tract. Individuals with these stigmata of the Peutz-Jeghers syndrome can be clinically tested for germ-line mutations in the STK11/LKB1 gene. Those found to carry a mutation may then benefit from screening for asymptomatic pancreatic neoplasia.

Third, most of these germ-line mutations, with the exception of those in the PRSS1 gene, are also associated with an increased risk of extrapancreatic malignancies. For example, the risk of melanoma in p16/CDKN2A gene mutation carriers is approximately 28% (95% confidence interval = 18% to 40%) by age 80. These extrapancreatic malignancies can also be screened for and, in the case of melanoma, preventative measures such as avoiding sun exposure can also be initiated.

Fourth, pancreatic cancers with microsatellite instability, the hallmark of DNA mismatch repair defects such as those produced by mutations in the hMLH1 and hMSH2 genes, often have a distinctive medullary histology. Medullary carcinomas are poorly differentiated; they have expanding borders and a prominent syncytial growth pattern. When a pancreatic cancer with this morphology is identified, the morphologic appearance of the cancer can be used to suggest that the patient may benefit from genetic counseling and possibly genetic testing.

Fifth, these germ-line genetic abnormalities may have therapeutic implications. For example, the protein product of the BRCA2 gene interacts with the protein products of the Fanconi anemia complementation genes (the FANC genes) to promote homologous recombination. As discussed subsequently in further detail, van der Heijden et al. have shown that pancreatic cancers with BRCA2 or other proximal FANC gene mutations are particularly sensitive to Mitomycin C and radiation—therapies known to cause DNA cross-linking and double strand breaks, respectively.

Finally, because of founder mutations, some of these genetic syndromes are more common in certain ethnic groups. For example, 1% of the Ashkenazi Jewish population carries the 6174delT BRCA2 gene mutation. Knowledge of these associations can help guide genetic testing.

 

 

 


Copyright ©  2010 Konstantin P Korchagin - All Rights Reserved

      k-korchagin@mail.ru  IСQ 566212547