CDH1 germline mutations are the major cause of hereditary diffuse gastric cancer (DGC). Carriers of CDH1 mutations can present multiple signet ring cell carcinoma foci at early age. Therefore, prophylactic total gastrectomy (PTG) is widely recommended. We report a family with a novel CHD1 mutation and analyze endoscopic and PTG findings among the mutation carriers.
Genetic CDH1 testing by Sanger was performed in a three-generation family with multiple relatives with DGC. Direct sequencing was offered to individuals at risk >18 years. Unaffected carriers were recommended PTG and preoperative esophagogastroduodenoscopy with random gastric biopsies (RGB). Each PTG specimen was wholly sectioned (median # cassettes: 203) to look for occult cancer and histopathology was compared to RGB findings.
A novel pathogenic variant in CDH1 c.48G>A (p.Q16Q) was identified in 28 family members, 16 male/12 female. Prior to variant identification, 6 obligate carriers were diagnosed with an advanced DGC, median age 56 (53-62) years and all died of the disease. After genetic testing, 8 asymptomatic carriers were found early-stage DGC in the PTG specimen, median age 25 (19-59) years. Age-specific frequency of DGC in carriers according to PTG is shown in the Table.Table:
|n = 8||n = 20|
|Age||DGC||Cumulative frequency||DGC||Cumulative frequency|
|n = 6||n = 8|
Histopathological RGB and PTG correlation was performed in 17 carriers attended at our institution (May 2013-Sept 2015). Median age at PTG was 34 (19-63) years. All preoperative RGB were negative, but one, which identified a single milimetric DGC foci. PTG specimens revealed one Tis and six T1a DGC, conferring RGB a predictive negative value (PNV) of 66% for DGC. Stage IA DGC had a median of 2.8 foci/gastrectomy, localized in the body (83%) and atrium (17%), with average diameter 0.73 mm and e-cadherin expression in 100% of the foci. No severe postoperative morbidity was recorded after a median follow-up of 29 (16-44) months.
PTG has changed the natural disease history in c.48G>A CDH1 carriers. Endoscopic RGB showed a low PNV for DGC and PTG is still highly recommended. More reliable screening methods are required in order to delay PTG in CDH1-mutation carriers.
Clinical trial identification
Legal entity responsible for the study
Vall d'Hebron Hospital
All authors have declared no conflicts of interest.