[Frontiers in Bioscience 3, d1148-1160, November 15, 1998]

Table of Conents
 Previous Section   Next Section


Shamlal Mangray and Thomas C King

Department of Pathology and Laboratory Medicine, Brown University School of Medicine, Providence, RI

Received 8/24/98 Accepted 9/4/98


Heritable pancreatic adenocarcinomas account for 3-10% of all pancreatic adenocarcinomas 3-10%. Heritable pancreatic adenocarcinoma can be divided into three subgroups (1) defined genetic syndromes associated with pancreatic adenocarcinoma; (2) clustering of pancreatic adenocarcinoma in a family not associated with a specific genetic syndrome; and (3) pancreatic adenocarcinoma in primary relatives of patients with non-pancreatic malignancies (3). While these groups can be defined operationally, there is potential overlap in that some family clusters may represent undiagnosed genetic syndromes and the association of some pancreatic adenocarcinomas with breast and ovarian cancer appears to be through the BRCA2 gene. Heritable cases are potentially helpful in identifying specific genes involved in pancreatic carcinogenesis. These patients may also be a useful study group for assessing new screening methods which might then be applied to the wider population.

3.1.Genetic syndromes predisposing to pancreatic adenocarcinoma

A number of well characterized genetic syndromes are associated with a significantly increased risk of developing pancreatic adenocarcinoma. Some of these, such as hereditary pancreatitis, are organ specific. Other syndromes, such as ataxia telangiectasia and Peutz-Jegher's Syndrome, are associated with the development of tumors at many sites in addition to the pancreas. In still other syndromes, such as hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome II) and familial atypical mole-malignant melanoma syndrome (FAMMM), pancreatic tumors are much less frequent than the characteristic tumors which define these syndromes (colon cancer and melanoma respectively). Although pancreatic adenocarcinoma is a relatively rare in some of these genetic diseases, it's lethality makes it a clinically important complication of these syndromes. The precise risk of developing pancreatic adenocarcinoma is difficult to define in most of these syndromes but available relative risk data is summarized in table 1.

Table 1. Heritable predisposition to pancreatic adenocarcinoma; AD = autosomal dominant; AR = autosomal recessive


Pattern ofInheritance

Relative Risk

Gene (Locus)

Familial Clustering

AD (subset)



BRCA2 (males)



BRCA2 (13q12)

Hereditary Pancreatitis



Unknown (7q35)

Ataxia Telangiectasia



ATM (11q22-23)




hMSH2 (2p15-16) hMLH1 (3p21-23)

FAMMM (subset)



p16INK4a (9p21)

Peutz-Jegher's syndrome



STK11 (19p13.3)

3.1.1. Hereditary pancreatitis

Hereditary pancreatitis is an autosomal dominant disorder characterized by recurrent, severe episodes of pancreatitis which is linked to a gene at 7q35 (7). Family studies of this condition are consistent with an autosomal dominant disorder with 80% penetrance. Predisposition to pancreatic adenocarcinoma may be due to chronic injury and regeneration by analogy to patients with nonhereditary chronic pancreatitis. Tumors usually develop later in life with an age distribution similar to that of sporadic tumors. Some caution must be used in making this analogy, however, since chronic pancreatitis is associated with some of the same environmental risk factors (ethanol and tobacco) as is pancreatic adenocarcinoma.

3.1.2. Ataxia telangiectasia

Ataxia telangiectasia is an autosomal recessive disorder. The gene responsible for the disorder resides on chromosome 11q22-23 and encodes for a protein similar to phosphatidylinositol 3' kinase which is involved in signal transduction, meiotic recombination and cell cycle control. Loss of one normal allele of this gene results in cells that are deficient in DNA repair and are prone to accumulate gene mutations. Patients are thus predisposed to many different types of cancers including leukemias, breast cancer, gastric cancers and pancreatic adenocarcinomas.

3.1.3. FAMMM syndrome

The FAMMM syndrome (familial atypical mole-malignant melanoma syndrome) is inherited in an autosomal dominant fashion and predisposes to the development of multiple malignant melanomas. This syndrome appears to be genetically heterogeneous with some but not all kindreds having germline mutations in the p16INK4a gene. p16INK4a is a negative regulator of cell cycle progression at the G1S restriction point (see below) and is frequently altered in sporadic pancreatic adenocarcinomas. Goldstein et al. found that the risk of developing pancreatic adenocarcinoma in FAMMM kindreds was increased by a factor of 13 in the kindreds with p16INK4a mutations (8). No excess cases of pancreatic adenocarcinoma occurred in the FAMMM kindreds with wild-type p16INK4a, however. Interestingly, the risk of developing invasive malignant melanoma did not differ significantly between the two groups with a 75x relative risk of developing melanoma in kindreds with the germline p16INK4a mutations versus 38x in the kindreds without p16INK4a mutations. These data provide compelling evidence of a direct role for p16INK4a gene alterations in the genesis of hereditary pancreatic adenocarcinoma.

3.1.4. Hereditary nonpolyposis colorectal cancer

HNPCC (hereditary nonpolyposis colorectal cancer) is inherited as an autosomal dominant trait predisposing affected individuals to colon cancer. Two genes which can produce this syndrome map to chromosome 2p and 3p respectively (9). In addition, affected individuals are at increased risk of cancers of breast, endometrium, ovary and pancreas, documented by pedigree studies (10). HNPCC is associated with replication errors and microsatellite instability resulting from an abnormality in DNA mismatch repair (3,11,12) .

3.1.5. Peutz-Jegher's Syndrome

Peutz-Jegher's syndrome is an autosomal dominant disorder characterized by multiple hamartomatous polyps of the gastrointestinal tract and mucocutaneous melanin deposits. The gene resulting in this disease, STK11, has been recently mapped but has not been fully characterized (13,14). This syndrome is associated with a significantly increased risk for developing tumors of the gastrointestinal tract at multiple sites. In a cohort of 31 patients followed by Giardiello et al. for 13 years, 15 developed some type of gastrointestinal cancer (48%). Four of these were pancreatic adenocarcinomas corresponding to a 100x relative risk compared to the general population estimated from this small group of patients (15).

3.2. Familial Pancreatic Cancer

Family clusters of pancreatic adenocarcinoma have been extensively reviewed by Lynch et al (16). Families in which three generations have been afflicted with pancreatic adenocarcinoma have been described, some in association with non-insulin dependent diabetes mellitus. Families with up to four affected siblings with pancreatic adenocarcinoma have also described and an autosomal dominant mode of transmission suggested. Since different authors have used different definitions of familial pancreatic adenocarcinoma to identify index cases, it is difficult to compare reported data (16). Family studies have shown an age presentation comparable to that of sporadic pancreatic adenocarcinoma with tumors developing relatively late in life. Since pancreatic adenocarcinoma is uncommon, but not rare, some case clustering in families may be coincidental. Conversely, since environmental carcinogens clearly predispose to pancreatic adenocarcinoma, some familial clustering may result from shared environmental risk factors rather than from genetic predisposition. Nevertheless, it seems clear that some families have a genetically determined increased risk of pancreatic adenocarcinoma. Such cases have been estimated to account for 3-10% of all cases of pancreatic adenocarcinoma. Some of these families may fit into previously defined genetic syndromes (e.g. HNPCC) (3,16). More uniform definition of familial clusters may aid in better defining the population at risk and ultimately in identifying the genes and/or environmental risk factors involved.

3.3. Pancreatic adenocarcinoma risk in families with other sporadic cancers

The final group of patients with potentially heritable pancreatic adenocarcinoma are those occurring in association with non-pancreatic cancer in the same the family. Of particular interest is the association with ovarian and breast cancers. Tulinius et al in their analysis of cancer risk of family members of randomly selected female breast cancer patients found that first degree male relatives had a 1.66 relative risk of developing pancreatic adenocarcinoma (17). This level of risk is orders of magnitude less than in most of the previously discussed genetic syndromes. An increased risk of ovarian cancer was also associated with a family history of pancreatic adenocarcinoma. Kerber and Slattery estimated that up to 4.8% of ovarian cancers were associated with a family history of pancreatic adenocarcinoma (18). Clearly there may be some overlap between these patients and those with defined genetic syndromes (see above). Nevertheless, further analysis of these kindreds may identify as yet undescribed genetic mutations involved in the pathogenesis of pancreatic adenocarcinoma.