Transcript The Duncan Chronicles: An American Family with HDGC

The Duncan Chronicles:
An American Family (My Family)
with HDGC
Jonathan P. Terdiman, MD
Professor of Clinical Medicine
University of California, San Francisco
My Grandfather: Phillip Gedankin
My Grandfather
• Born in Slutzk, Belorussia in 1903
• Studied violin, and at age 9 was sent to live in
Kiev to study for 5 years at the conservatory
• Played for the Russian Opera orchestra
• Escaped to Poland in a hay wagon in 1921 with
$300 and a Gagliano violin, and then on to the
USA
• Kansas City and then Omaha to play with the Art
Randall orchestra
My Grandparents: Phillip and
Sara Brookstein in 1924
My Uncles and My Mother
My family pedigree as I knew it during my medical
training
Gastric Cancer: Adenocarcinoma
• 2nd most common cancer worldwide
– 10% of all cancers, 15% of all cancer deaths
• Dramatic variations in incidence and
prevalence
– 80-100/100, 000 in Asia, Eastern Europe vs 210/100, 000 in USA
• Screening in endemic areas may decrease
mortality by up to 50%
Gastric Cancer: Risk Factors
• H. pylori infection (2-3 fold)
• Smoked foods, pickled foods, salted fish
and meat
• Tobacco and alcohol
• Male sex (2 fold)
• Age
• Family history (1.5-3 fold)
• Pernicious anemia
Gastric adenocarcinoma: Histology
• Intestinal
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Men
Older age
Associated with intestinal metaplasia
Antral/distal stomach
Better prognosis
• Diffuse (signet ring cell, linnitus plastica)
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Women
Younger age
Proximal tumors, diffuse growth
Poorer prognosis
Butchie, Yvonne and the Girls
My cousin Beth dies in 1999 of colorectal cancer at
age 41
Beth Duncan: Mother of three
Could we have Lynch Syndrome?
Could we have Lynch Syndrome?
• Lifetime risk for gastric cancer is 5-6%
– No genotype/phenotype correlation
– No family heterogeneity
– Higher risk in endemic areas
• Gastric cancers are intestinal type
• No recommended screening or surveillance
• Answer for the Duncans: NO
– Beth has a signet-ring, mucinous carcinoma c/w
Lynch
– Beth’s tumor, however, was microsatellite stable with
normal expression of MSH2, MLH1, MSH6
New Years Day 2000: My uncle Donald dies of
“diffuse” gastric cancer
Donald Duncan: WW II Combat
Veteran
• Corporal in Marine
Corps, 1st Division:
1943-1946
• Participated in action
against the enemy
– New Guinea
– Cape Gloucester, New
Britain
– Peleliu
– Okinawa
The Plot Thickens…
Do the Duncans have hereditary
gastric cancer?
I undergo my first EGD/colonoscopy
Familial Gastric Cancer
• Any FDR (1.5-3 fold risk)
• Known syndromes
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Lynch syndrome = 5-6% lifetime risk
FAP = 0.5-1% lifetime risk
PJS
Li-Fraumeni
• Hereditary gastric cancer
– Intestinal type
– Diffuse type
• Described in 1998 in a large Maori family in New
Zealand (Guilford P. Nature 1998;392:402-5)
The straw that breaks the camel’s back: my cousin
Erin dies of diffuse gastric cancer in 2007
Erin Duncan: Mother of two dies at
age 45
Hereditary Diffuse Gastric Cancer
HDGC: The Syndrome
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Rare, accounting for ~ 1% of gastric cancer
Autosomal dominant inheritance
Worldwide distribution across many ethnicities
50-80% penetrance of gastric cancer
Diffuse-type gastric cancer with signet-ring cells
Increased risk for lobular carcinoma of the
breast and maybe colorectal cancer
– Risk of 40-50% for breast cancer by age 80
HDGC
(Pharoah P. Gastroenterology, 2001; Blair V. CGH, 2006; Kaurah P. Jama,
2007)
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Gastric cancer risk in excess of 70%
Risk is greater in women than men
Mean age of cancer diagnosis 40-45
Risk advances with age
– Youngest described case at 14 years, oldest at age
82
– Age 20 risk is < 1%
– Age 30 risk is < 5%
– Age 50 risk is 20% in men, but 50% in women
– Age 70, risk is 40% in men and 65% in women
– Age 80, risk is 65% in men and 85% in women
HDGC Genetics
Oliveira C. Hum Mol Genet, 2009
• Germline mutation of E-cadherin (CDH1)
• Germline mutation can be identified in 3050% of HDGC families
– Higher mutation detection rate in locations
with low GC incidence
• > 80 different mutations so far
– 50% are inactivating and 20-30% greatly
reduce gene function
– 5% are large genomic rearrangements
HDGC Genomics
Oliveira C. Gastro, 2009
• Neoplasia requires inactivation of 2nd allele
– 2nd events include promoter methylation, LOH
– LOH as second event may be more common
in advanced disease
• Loss of gene expression in early lesions,
but not surrounding normal tissue
• No other genomic events identified in early
lesions
HDGC Genomics
Oliveira C. Gastro, 2009; Humar B. Cancer Res, 2009
• Loss of CDH1 function
leads to deficient
adhesion
• Loss of attachment of
gastric stem cells to their
niches
• Loss correct spindle
orientation during
asymmetric stem cell
division
• Hypoproliferation of early
lesions
HDGC Histology
Barber ME. J Pathol, 2008
• Multiple foci (tens to
hundreds) of diffuse, tiny
(< 100 cells to < 1mm)
signet-ring cell ca, esp in
gastric body or fundus,
0.01-3% of gastric
surface involved
• Cancers are initially
superficial (T1a), but subepithelial, clonally distinct
• Prolonged indolent phase
before invasion, then
rapid progression
Presymptomatic CDH1 Testing
• Criteria for testing
– Two 1st or 2nd degree relatives with diffuse
gastric cancer, one < age 50 years
– Three cases of diffuse gastric cancer at any
age
• Testing yield
– CDH1 mutations found in 30-50% meeting
criteria
– CDH1 mutations in < 10% in diffuse gastric
cancer < age 50 w/o family history
HDGC: Cancer Prevention
• EGD surveillance (Hebbard PC. Ann Surg Oncol, 2009; Barber
ME. J Pathol, 2008)
– Standard white light EGD not adequate
• 42 CDH1 mutation carriers have undergone EGD with biopsy
prior to gastrectomy
• 41/42 with confirmed early cancer at gastrectomy, but only
6/42 with evidence on endoscopic biopsy
– Chromendoscopy with Congo-red and methylene blue
is more sensitive, but not clear it is enough
• 33 patients with normal EGD
• 10 of 33 patients found to have early gastric cancers with
chromo, but foci less < 4 mm missed still (Gut, 2005)
HDGC: Cancer Prevention
• Stanford HDGC kindred (Annals of Surg, 2007)
• Six patients with CDH-1 mutations
• Pre-op
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EGD with multiple random biopsies
High magnification endoscopy
EUS
CT and PET
• Operative histology
– All six with multiple foci of T1 cancers, all were
T1N0M0
HDGC: Cancer Prevention
• Total gastrectomy is only reliable prevention with
long-term survival > 95% for T1 disease
• Operative risk is < 1%
• Morbidity can be considerable
– Malnutrition
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Early satiety
Loss of > 10% of body weight
Vitamin deficiencies (Fe, B12, Ca++, Vit D, folate)
Rapid transit, dumping, fat malabsorption, bacterial
overgrowth
– Quality of life
HDGC Surveillance for Gene
Carriers
(Kaurah P. Jama, 2007)
• Endoscopy from age 15-20 q year
– Chromoendoscopy?
– Multiple biopsies as cancer detection is a function of
biopsy number-25+, concentrate on fundus and body
• Prophylactic gastrectomy at age 20
– Ongoing EGD surveillance every 6 months in those
who refuse surgery
• Yearly mammography and breast MRI or USG
starting at age 30, ? prophylactic surgery
• Colonoscopy q 3-5 years starting at age 30
years
Management of at risk individuals
in which gene testing is not
informative, ie causal mutation
cannot be found???
Endoscopic surveillance vs.
prophylactic surgery
Surveillance Questions: How
often, special methods such as
chromo, NBI, EMR?
Time for a family reunion…we learn about distant relatives
My Mom (age 74) and Uncle Arnold (age 82)
are alive and well…but everybody is
nervous…
Duncans at Risk
• We attempt a
germline CDH1
mutational analysis
– My mom’s blood
– Using archival tissues
• No mutation is found
by Dr. David
Huntsman and
colleagues at the
Vancouver Cancer
Center
The resolution of this story…none
yet…but I will keep trying…