The impact of prophylactic total gastrectomy on health-related quality of life: a prospective cohort study.

BACKGROUND: The advice to individuals with identified CDH1 mutations is generally to undertake prophylactic total gastrectomy (PTG). This study evaluated the effect of PTG on health-related quality of life (HRQL) in asymptomatic individuals with identified CDH1 mutations at high risk for gastric cancer. METHODS: Individuals with hereditary diffuse gastric cancer (HDGC) were recruited to a prospective, multicenter UK study. Questionnaires, including the European Organization for Research and Treatment for Cancer core Quality-of-Life Questionnaire (EORTC QLQ C30); the gastric cancer specific module (EORTC QLQ STO22); and the 36-item short form health survey version 2.0, were completed before and at regular intervals after surgery. RESULTS: Sixty individuals fulfilled HDGC criteria; 38 (63%) had a CDH1 mutation and 32 (53%) underwent PTG. At baseline, there was no significant difference in mental health depending on CDH1 mutation status and treatment preference. Physical functioning reduced in the first month after surgery but recovered to baseline by 12 months. Similarly mental functioning reduced in the first month after surgery but recovered by 3 to 9 months. However, specific symptoms were identified, such as diarrhoea (70%), fatigue (63%), discomfort when eating (81%), reflux (63%), eating restrictions (45%), and body image (44%), which persisted after PTG. CONCLUSIONS: Patients contemplating prophylactic gastrectomy can be reassured about the long-term HRQL outcomes, but some residual symptoms require adjustment.

Germline CDH1 deletions in hereditary diffuse gastric cancer families.

Germline CDH1 point or small frameshift mutations can be identified in 30-50% of hereditary diffuse gastric cancer (HDGC) families. We hypothesized that CDH1 genomic rearrangements would be found in HDGC and identified 160 families with either two gastric cancers in first-degree relatives and with at least one diffuse gastric cancer (DGC) diagnosed before age 50, or three or more DGC in close relatives diagnosed at any age. Sixty-seven carried germline CDH1 point or small frameshift mutations. We screened germline DNA from the 93 mutation negative probands for large genomic rearrangements by Multiplex Ligation-Dependent Probe Amplification. Potential deletions were validated by RT-PCR and breakpoints cloned using a combination of oligo-CGH-arrays and long-range-PCR. In-silico analysis of the CDH1 locus was used to determine a potential mechanism for these rearrangements. Six of 93 (6.5%) previously described mutation negative HDGC probands, from low GC incidence populations (UK and North America), carried genomic deletions (UK and North America). Two families carried an identical deletion spanning 193 593 bp, encompassing the full CDH3 sequence and CDH1 exons 1 and 2. Other deletions affecting exons 1, 2, 15 and/or 16 were identified. The statistically significant over-representation of Alus around breakpoints indicates it as a likely mechanism for these deletions. When all mutations and deletions are considered, the overall frequency of CDH1 alterations in HDGC is approximately 46% (73/160). CDH1 large deletions occur in 4% of HDGC families by mechanisms involving mainly non-allelic homologous recombination in Alu repeat sequences. As the finding of pathogenic CDH1 mutations is useful for management of HDGC families, screening for deletions should be offered to at-risk families.

Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research.

25-30% of families fulfilling the criteria for hereditary diffuse gastric cancer have germline mutations of the CDH1 (E-cadherin) gene. In light of new data and advancement of technologies, a multidisciplinary workshop was convened to discuss genetic testing, surgery, endoscopy and pathology reporting. The updated recommendations include broadening of CDH1 testing criteria such that: histological confirmation of diffuse gastric criteria is only required for one family member; inclusion of individuals with diffuse gastric cancer before the age of 40 years without a family history; and inclusion of individuals and families with diagnoses of both diffuse gastric cancer (including one before the age of 50 years) and lobular breast cancer. Testing is considered appropriate from the age of consent following counselling and discussion with a multidisciplinary team. In addition to direct sequencing, large genomic rearrangements should be sought. Annual mammography and breast MRI from the age of 35 years is recommended for women due to the increased risk for lobular breast cancer. In mutation positive individuals prophylactic total gastrectomy at a centre of excellence should be strongly considered. Protocolised endoscopic surveillance in centres with endoscopists and pathologists experienced with these patients is recommended for: those opting not to have gastrectomy, those with mutations of undetermined significance, and in those families for whom no germline mutation is yet identified. The systematic histological study of prophylactic gastrectomies almost universally shows pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. Expert histopathological confirmation of these early lesions is recommended.

Pregnancy after prophylactic total gastrectomy.

Hereditary diffuse gastric cancer is an autosomal dominant inherited cancer predisposition syndrome characterized by susceptibility to diffuse gastric and lobular breast cancers. Since current screening options for diffuse gastric cancer are ineffective, prophylactic total gastrectomy (PTG) is a recommended option for unaffected germline CDH1 mutation carriers. It is unknown whether pregnancy after surgery is possible or advisable due to potential maternal nutritional deficiencies. In this report we describe the pregnancy outcomes in three CDH1 mutation positive women after PTG and in a CDH1 mutation negative woman after total gastrectomy for early gastric cancer.