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The Duncan Chronicles: An American Family (My 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

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The Duncan Chronicles: An American Family (My Family) with HDGC

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  1. The Duncan Chronicles:An American Family (My Family) with HDGC Jonathan P. Terdiman, MD Professor of Clinical Medicine University of California, San Francisco

  2. My Grandfather: Phillip Gedankin

  3. 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

  4. My Grandparents: Phillip and Sara Brookstein in 1924

  5. My Uncles and My Mother

  6. My family pedigree as I knew it during my medical training

  7. 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 2-10/100, 000 in USA • Screening in endemic areas may decrease mortality by up to 50%

  8. 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

  9. Gastric adenocarcinoma: Histology • Intestinal • Men • Older age • Associated with intestinal metaplasia • Antral/distal stomach • Better prognosis • Diffuse (signet ring cell, linnitus plastica) • Women • Younger age • Proximal tumors, diffuse growth • Poorer prognosis

  10. Butchie, Yvonne and the Girls

  11. My cousin Beth dies in 1999 of colorectal cancer at age 41

  12. Beth Duncan: Mother of three

  13. Could we have Lynch Syndrome?

  14. 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

  15. New Years Day 2000: My uncle Donald dies of “diffuse” gastric cancer

  16. 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

  17. The Plot Thickens… Do the Duncans have hereditary gastric cancer? I undergo my first EGD/colonoscopy

  18. Familial Gastric Cancer • Any FDR (1.5-3 fold risk) • Known syndromes • 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)

  19. The straw that breaks the camel’s back: my cousin Erin dies of diffuse gastric cancer in 2007

  20. Erin Duncan: Mother of two dies at age 45

  21. Hereditary Diffuse Gastric Cancer

  22. HDGC: The Syndrome • 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

  23. HDGC(Pharoah P. Gastroenterology, 2001; Blair V. CGH, 2006; Kaurah P. Jama, 2007) • 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

  24. HDGC GeneticsOliveira C. Hum Mol Genet, 2009 • Germline mutation of E-cadherin (CDH1) • Germline mutation can be identified in 30-50% 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

  25. HDGC GenomicsOliveira 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

  26. HDGC GenomicsOliveira 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

  27. HDGC HistologyBarber 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 sub-epithelial, clonally distinct • Prolonged indolent phase before invasion, then rapid progression

  28. 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

  29. 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)

  30. HDGC: Cancer Prevention • Stanford HDGC kindred (Annals of Surg, 2007) • Six patients with CDH-1 mutations • Pre-op • 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

  31. 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 • 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

  32. 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

  33. 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?

  34. Time for a family reunion…we learn about distant relatives

  35. My Mom (age 74) and Uncle Arnold (age 82) are alive and well…but everybody is nervous…

  36. 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

  37. The resolution of this story…none yet…but I will keep trying…

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