Familial Pancreatic Cancer

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					                                     Familial Pancreatic Cancer
                               Chanjuan Shi, MD, PhD; Ralph H. Hruban, MD; Alison P. Klein, PhD

● Context.—Approximately 5% to 10% of individuals with                   Data Sources.—Published literature on familial aggre-
pancreatic cancer report a history of pancreatic cancer in            gation of pancreatic cancer and familial exocrine pancre-
a close family member. In addition, several known genetic             atic tumors.
syndromes, such as familial breast cancer (BRCA2), the                   Conclusions.—Even in the absence of predictive genetic
Peutz-Jeghers syndrome, and the familial atypical multiple            testing, the collection of a careful, detailed family history
mole melanoma syndrome, have been shown to be asso-                   is an important step in the management of all patients with
ciated with an increased risk of pancreatic cancer. The               pancreatic cancer. While most pancreatic cancers that
                                                                      arise in patients with a family history are ductal adenocar-
known genes associated with these conditions can explain
                                                                      cinomas, certain subtypes of pancreatic cancer have been
only a portion of the clustering of pancreatic cancer in              associated with familial syndromes. Therefore, the histo-
families, and research to identify additional susceptibility          logic appearance of the pancreatic cancer itself, and/or the
genes is ongoing.                                                     presence and appearance of precancerous changes in the
  Objective.—To provide an understanding of familial pan-             pancreas, may increase the clinical index of suspicion for
creatic cancer and the pathology of familial exocrine pan-            a genetic syndrome.
creatic cancers.                                                         (Arch Pathol Lab Med. 2009;133:365–374)

                      EPIDEMIOLOGY                                    had also smoked for more than 20 years (OR of 5.3 [95%
   Case reports of families in which multiple family mem-             CI, 2.1–13.4]) than for individuals who did not smoke or
bers have been diagnosed with pancreatic cancer provided              had smoked for less than 20 years (OR of 2.2 [95% CI, 1.0–
the first evidence that pancreatic cancer can aggregate in             7.9]).10 While these results could represent a synergistic
families. The first of these was published by MacDermott               effect between smoking and a pancreatic cancer suscep-
and Kramer1 in 1973 and described a family in which 4                 tibility gene, a portion of this increased risk may also be
of 6 siblings had pancreatic cancer. Many additional case             due to the clustering of cigarette smoking, a known risk
reports followed.2–7 In 1990, Lynch et al8 reported a series          factor of pancreatic cancer, in families.
of 18 kindreds with familial pancreatic cancer from a large              In addition to these case-control studies, prospective co-
familial cancer registry.                                             hort studies, which are not subject to recall biases, have
   These initial studies were followed by more rigorous               also demonstrated an increased risk of pancreatic cancer
observational case-control and cohort studies, which are              among persons with a family history of pancreatic cancer.
outlined in Table 1. Ghadirian et al9 found that 7.8% of all          As part of the American Cancer Society’s Cancer Preven-
patients with pancreatic cancer and only 0.6% of controls             tion Study 2, Coughlin et al11 reported an increased risk
had a family history of pancreatic cancer, a 13-fold differ-          of developing pancreatic cancer for individuals who re-
ence, with no differences in environmental risk factors be-           ported a positive family history of pancreatic cancer at
tween the 2 groups. A population-based, US study (Atlan-              baseline, with an RR of 1.5 (95% CI, 1.1–2.1) after adjust-
ta, Detroit, and New Jersey) also reported that individuals           ing for age. Furthermore, a population-based cohort study
with a first-degree relative with a pancreatic cancer had              demonstrated that the risk of pancreatic cancer increased
an increased risk of developing pancreatic cancer, with an            1.72-fold (95% CI, 1.13–2.54) for individuals with a parent
odds ratio (OR) of 3.2 (95% confidence interval [CI], 1.8–             with pancreatic cancer. The risk was not elevated when a
5.6). This increase in risk was higher among individuals              more distant relative had been diagnosed with pancreatic
with a first-degree relative with pancreatic cancer who                cancer. Thus, both case-control and cohort studies strongly
                                                                      support the hypothesis that familial aggregation and ge-
                                                                      netic susceptibility play an important role in the devel-
  Accepted for publication October 8, 2008.                           opment of pancreatic cancer. However, the relative contri-
  From the Departments of Pathology (Drs Shi, Hruban, and Klein)
and Oncology (Drs Hruban and Klein), The Sol Goldman Pancreatic       bution of genetic risk factors and environmental risk fac-
Cancer Research Center, The Johns Hopkins University, Baltimore,      tors to pancreatic cancer risk that cluster within the fam-
Maryland; and the Department of Epidemiology, Bloomberg School        ilies (ie, smoking) remains unclear.
of Public Health, The Johns Hopkins University, Baltimore, Maryland      The initial case reports and early population-based
(Dr Klein).                                                           studies were followed by the establishment of family can-
  The authors have no relevant financial interest in the products or
                                                                      cer registries, including the National Familial Pancreas Tu-
companies described in this article.
  Reprints: Alison P. Klein, PhD, Departments of Oncology and Pa-     mor Registry (NFPTR). The NFPTR was founded in 1994
thology, The Johns Hopkins School of Medicine, 1550 Orleans St,       at The Johns Hopkins Hospital (Baltimore, Maryland) as a
Room 303, Baltimore, MD 21212 (e-mail: aklein1@jhmi.edu).             resource for advancing our understanding of familial pan-
Arch Pathol Lab Med—Vol 133, March 2009                                                      Familial Pancreatic Cancer—Shi et al 365
                                        Table 1.   Familial Aggregation Studies of Pancreatic Cancer
               Study Design, Location                     Study Population                    Resulta                     Source, y
   Case-control, population-based,                       179 cases                     OR    13-fold (P      .001)b Ghadirian et al,9 1991
     Quebec, Canada                                      179 controls
   Case-control, h
				
DOCUMENT INFO
Description: CONTEXT: Approximately 5% to 10% of individuals with pancreatic cancer report a history of pancreatic cancer in a close family member. In addition, several known genetic syndromes, such as familial breast cancer (BRCA2), the Peutz-Jeghers syndrome, and the familial atypical multiple mole melanoma syndrome, have been shown to be associated with an increased risk of pancreatic cancer. The known genes associated with these conditions can explain only a portion of the clustering of pancreatic cancer in families, and research to identify additional susceptibility genes is ongoing. OBJECTIVE: To provide an understanding of familial pancreatic cancer and the pathology of familial exocrine pancreatic cancers. DATA SOURCES: Published literature on familial aggregation of pancreatic cancer and familial exocrine pancreatic tumors. CONCLUSIONS: Even in the absence of predictive genetic testing, the collection of a careful, detailed family history is an important step in the management of all patients with pancreatic cancer. While most pancreatic cancers that arise in patients with a family history are ductal adenocarcinomas, certain subtypes of pancreatic cancer have been associated with familial syndromes. Therefore, the histologic appearance of the pancreatic cancer itself, and/or the presence and appearance of precancerous changes in the pancreas, may increase the clinical index of suspicion for a genetic syndrome.
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