Hereditary Pancreatitis

Children and adolescents with hereditary pancreatitis (HP) may develop severe pancreatitis
at a young age, often in childhood or adolescence, with a resultant 50-fold to 80-fold
increased risk of PC developing over their lifetime. HP results from germline or new
somatic mutations in the PRSS1 cationic trypsinogen gene ( Lowenfels et al, 1997 ).
Approximately 40% of those with HP will develop PC when the additional risk factor of
cigarette smoking is added. The risk of cancer seems to be limited to pancreatic cancers and
not tumors in other organs.

Hereditary Nonpolyposis Colorectal Cancer

Hereditary nonpolyposis colorectal cancer is an autosomal dominant inherited disease that
predisposes affected persons to colorectal cancer and PC ( Hruban et al, 2002 ). It is usually
caused by germline mutations in a number of DNA mismatch repair genes. Of the inherited
syndromes associated with an increased risk of PDAC, hereditary nonpolyposis colorectal
cancer is the least strongly linked to pancreatic cancer.

Hereditary Breast and Ovarian Cancer

Patients with germline BRCA2 mutations have up to a 10-fold increased risk (range, 3.5- to
10-fold) of PC, even in patients without a strong family history of breast cancer. Goggins
and colleagues (1996) identified germline BRCA2 mutations in 7% of sporadic
(nonfamilial) PC patients screened, none of whom had a family history of breast cancer or
PC. BRCA1 mutation carriers followed in a breast and ovarian cancer evaluation center, had
a threefold increased risk of PC, a twofold increased risk for colon cancer, a fourfold
increased risk for gastric cancer and a 120-fold increased risk for fallopian tube cancer
compared with SEER population-based estimated risk ( Brose et al, 2002 ).

Familial Atypical Multiple Mole and Melanoma Syndrome

Familial atypical multiple mole and melanoma (FAMMM) syndrome is rare condition
associated with p16 germline mutations, a tumor suppressor gene that may be mutated or
may have its expression altered by posttranscriptional methylation. The syndrome
predisposes affected individuals to melanomas, multiple nevi, atypical nevi, and PC
( Lynch et al, 1990 ). Those with FAMMM have a 20- to 34-fold increased risk of PC over
their lifetime.

Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome is a rare autosomal dominant disease associated with alterations in
the STK11 gene, in which affected individuals develop hamartomatous polyps of the
gastrointestinal tract and lip freckles referred to as mucocutaneous melanocytic
macules ( Hruban et al, 2002 ). Individuals with this syndrome have a roughly 100-fold
increased risk of developing PC ( Giardiello et al, 2000 ), and they also appear to have a
tendency to form intraductal papillary mucinous neoplasms.

Ataxia-Telangiectasia
Ataxia-telangiectasia is an autosomal recessive inherited disorder associated
with ATM gene mutations, in which affected persons present with cerebellar ataxia,
conjunctival telangiectasias, a hypofunctioning thymus gland, and oculomotor
abnormalities. An association between ataxia-telangectasia and the subsequent
development of PC has been reported, but it is less well established than with the other five
familial syndromes ( Lynch et al, 1996 ).

Tobacco Exposure
Cigarette smoking has been definitively identified as a causative agent in 25% to 35% of
the cases of PDAC and is the most consistently reported risk factor ( Iodice et al,
2008 ; Jemal et al, 2009 , Lowenfels et al, 2004 ). Smoking is associated with increased risk
of PC in at least 29 epidemiologic studies ( Silverman et al, 1994 ), and smokers have a
70% increased risk of PC compared with nonsmokers. Smoking habits in the 15 years
preceding the diagnosis of PC appear to be more relevant to increased risk, whereas former
smokers who have quit for more than 13 years decrease their PC risk to that of lifetime
nonsmokers ( Howe et al, 1991 ). A meta-analysis of 83 epidemiologic studies found that
the overall relative risk of PC in current and former smokers was 1.74, a 74% increased risk
of PC in these groups ( Iodice et al, 2008 ). A retrospective analysis comparing smoking in
cases of familial PC and sporadic PC found that 57% and 60%, respectively, of patients
reported prolonged cigarette smoking, with an overall mean of 35 packs/year history ( Yeo
et al, 2009 ).

Prospective and retrospective studies have found that the risk of PC increases consistently
with cigarette smoking but inconsistently with cigar or pipe smoking ( Wynder, 1975 ).
Cigar consumption has increased 233% between 2000 and 2011; regular cigar smokers
have 4 to 10 times the risk of dying from laryngeal, oral, or esophageal cancers (and likely
PC) than do nonsmokers ( Centers for Disease Control and Prevention, 2013 ).

A dose-response relationship between PDAC and the number of cigarettes consumed has
been documented in several investigations ( Ahlgren, 1996 ; Howe et al, 1991 ). For current
smokers who also have a family history of pancreatic cancer, the relative risk of PC has
been reported to be as high as 8.23 ( Schenk, 2001 ). Lowenfels and colleagues
(1997) found that individuals with familial PC tend to smoke more than those with sporadic
PC. These observations raise the possibility that smoking is interactive, perhaps
multiplicatively, with genetic mutations known to be present in persons with familial PC.
Postmortem examinations of the pancreatic ducts of smokers have found widespread ductal
hyperplasia, that is, lesions termed pancreatic intraepithelial neoplasia , which are
considered to be premalignant lesions. Neugut and associates (1995) found a relationship
between cigarette smoking and the development of PC as a second malignancy in patients
with a smoking-related first malignancy, such as lung, head and neck, or bladder cancer.
This relationship is likely due to overlapping smoking-related genetic mutations among
these different malignancies.

Smoking is most common in the least educated; in 2012, adults with a Bachelor’s degree
were less likely to be current smokers than those adults with less education. ( National
Center for Health Statistics, 2012 ). Eighteen percent of adults and 14% of high school
students in the United States report current smoking Centers for Disease Control and
Prevention. A 2003 study of adults aged 30 to 39 years that included parental occupation,
adult educational attainment, and household income as indicators of socioeconomic status
(SES) found that those of lower SES were more likely to start smoking and to become
regular smokers and were less likely to quit smoking than their higher SES counterparts
( Gilman et al, 2003 ).