Table Of ContentGiovanni Corso · Franco Roviello Editors
Spotlight on
Familial and
Hereditary
Gastric Cancer
Spotlight on Familial and Hereditary
Gastric Cancer
Giovanni Corso (cid:129) Franco Roviello
Editors
Spotlight on Familial
and Hereditary Gastric
Cancer
Editors
Giovanni Corso Franco Roviello
Section of General Surgery and Surgical Section of General Surgery and Surgical
Oncology Oncology
Department of Medical, Surgical Sciences Department of Medical, Surgical Sciences
and Neuroscience and Neuroscience
University of Siena University of Siena
Siena, Italy Siena, Italy
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ISBN 978-94-007-6569-6 ISBN 978-94-007-6570-2 (eBook)
DOI 10.1007/978-94-007-6570-2
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“Don’t let your life be barren. Be useful.
Make yourself felt. Shine forth with the torch
of your faith and your love”
Foreword
Henry T. Lynch
In 2008, the last year for which international cancer fi gures were available, worldwide
gastric cancer incidence estimates were 989,000 new cases and 737,000 deaths
(Ferlay et al. 2010). The estimated incidence of gastric cancer in the United States
for 2013 is 21,600 with a mortality of 10,990 (Siegel et al. 2013). The two major
histological types of gastric cancer (Alberts et al. 2003; Lauren 1965) are: (1) intestinal ,
which is more common and more often associated with environmental factors
and Helicobacter pylori ; and (2) diffuse gastric cancer (DGC), which is less common
and more likely to be associated with host factors (Lauren 1965).
Hereditary diffuse gastric cancer (HDGC) was fi rst described in 1964 in three
Māori families from New Zealand (Jones 1964). In 1998, among these same Māori
families, Guilford and colleagues (Guilford et al. 1998) fi rst identifi ed that this auto-
somal dominantly inherited disorder is due to mutations of the E-cadherin (C DH1 )
gene. It is estimated that about 40 % of families with HDGC (defi ned as families
from low-incident populations with two or more gastric cancers and one proven
DGC diagnosed in an individual less than 50 years of age) will have a pathogenic
CDH1 mutation (Kaurah et al. 2007). Oliveira et al. (Oliveira et al. 2009) indicated
that germline C DH1 point or small frameshift mutations can be found in 30–50 %
of HDGC families. The penetrance of HDGC is approximately 70 % in CDH1
mutation carriers (Kaurah et al. 2007; Ziogas and Roukos 2009). In addition, women
from HDGC families who test positive for the C DH1 mutation show a lifetime risk
of approximately 40 % for lobular carcinoma of the breast (Keller et al. 1999;
Schrader et al. 2008).
The sine qua non for diagnosis of HDGC is documentation of the CDH1 germ-
line mutation in the patient/family. In 2010, the International Gastric Cancer
Linkage Consortium (IGCLC) published updated recommendations (Fitzgerald
et al. 2010) for genetic testing, surgery, endoscopy, and pathology for HDGC with
CDH1 mutations. New testing criteria state that individuals diagnosed with DGC
before the age of 40 years should be included even if there is no family history, as
should families with diagnoses of both DGC, including one case before the age
of 50 years, and lobular breast cancer. Testing is considered appropriate from the
age of consent on. Counseling and discussion with a multidisciplinary team is
vii
viii Foreword
necessary before testing occurs. Women with a C DH1 mutation should have annual
mammography and breast MRI beginning at the age of 35, because of the increased
risk for lobular breast cancer.
Because DGC lesions are submucosal, current screening methods such as upper
endoscopy with multiple biopsies are inadequate for early diagnosis (Alberts et al.
2003). Since its mortality rate is high once diagnosed at the symptom stage, prophy-
lactic total gastrectomy is a viable option for mutation carriers (Huntsman et al.
2001; Lynch et al. 2008a, b; Ziogas and Roukos 2009), and such surgery at a center
of excellence should be strongly considered for these individuals. Deciding to
undergo prophylactic total gastrectomy may be an extremely problematic emotional
experience (Kaurah et al. 2007; Lynch et al. 2005, 2008b) which requires compas-
sionate genetic counseling. Endoscopic surveillance at centers with experienced
endoscopists and pathologists is recommended for those opting not to have prophy-
lactic gastrectomy, those who have mutations of undetermined signifi cance, and
those who are members of families in which a germline mutation has not yet been
identifi ed (Pedrazzani et al. 2007).
This book, Spotlight on Familial and Hereditary Gastric Cancer , is organized as
follows: (1) the fi rst three chapters deal with general issues; (2) the next seven chap-
ters deal with genetics and epigenetics; (3) two chapters deal with pathology; (4) the
all-important section on management harbors a clinical thrust and contains four
chapters; and, fi nally, (5) two appendices are included that contain useful supple-
mentary fi gures.
Major attention by us has been given to the chapter by Giovanni Corso et al.
regarding clinical management, which is a very well-written treatise on the subject,
and which clearly depicts the need for clinicians to understand the differential diag-
nosis of familial and hereditary forms of gastric cancer. Careful attention has been
given to the importance of environmental factors when discussing familial and
hereditary etiologic contributing factors. In the case of the C DH1 mutation, prophy-
lactic gastrectomy for HDGC is discussed. For carriers of a C DH1 truncating muta-
tion, the importance of prophylactic gastrectomy is considered, while among C DH1
missense mutation carriers, the prophylactic surgical approach is debatable. In their
discussion of familial intestinal gastric cancer, Corso et al. cite an interesting study
by Chung et al. (Chung et al. 2012) that suggests that in patients from a gastric can-
cer high-incidence population and from families with intestinal gastric cancer clus-
tering, the risk relevant to the gastric cancer stage of diagnosis was not increased in
patients with 2- or 3-year intervals between endoscopies, whereas it was increased
in those with 4- or 5-year screening intervals. However, Corso et al. also note that
other studies have found annual endoscopy to be useful.
Chapter 6 by Guilford and Humar deals with molecular mechanisms of HDGC
initiation and progression. Historically, it was Guilford who identifi ed the C DH1
germline mutation for HDGC. Among C DH1 germline mutation carriers, these
authors note that the stomachs contain multifocal, stage T1a signet ring cell carci-
nomas which are generally indolent but which show an unpredictable tendency
toward rapid progression. They note that the initial development of these cancer foci
is triggered by down-regulation of the second C DH1 allele, largely through
Foreword ix
epigenetic mechanisms. They state that the loss of E-cadherin expression has an
effect on the orientation of the mitotic spindle and hypothesize that some proliferat-
ing cells in the gastric gland divide out of the epithelial plane and penetrate the
lamina propria .
This book will be of great interest to medical and surgical oncologists and gas-
troenterologists. It will also be of interest to most specialists, particularly patholo-
gists, genetic counselors, and basic and clinical researchers.
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