Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.

IMPORTANCE: E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. OBJECTIVES: To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. DESIGN, SETTING, AND PARTICIPANTS: Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. MAIN OUTCOMES AND MEASURES: Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. RESULTS: Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. CONCLUSIONS AND RELEVANCE: This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.

Family matters: examining a multi-family group intervention for women with BRCA mutations in the scope of genetic counselling.

The availability of family-centred services for women genetically at-risk for breast and ovarian cancer (BRCA) due to deleterious genetic mutations is still scarce, despite the distress that these women and their families may experience. This study describes a multi-family group intervention for women who tested positive for BRCA mutations and their families. Methods include a time-limited psycho-educational programme involving educational and support components and consisting of four semi-structured multi-family sessions. Three families (a total of nine people) attended the programme in genetic counselling for hereditary cancers at a Portuguese public hospital. A focus group interview was performed 1 month after the last session to assess both the practical and the psychosocial impacts and to collect suggestions from participants. The present paper focuses on the practical aspects of the intervention, its development and its evaluation. Participants reported that the programme is well-structured and that responds to the needs of patients and their families by improving coping skills and medical awareness in the adaptation to genetic illness. Results reinforce the need to integrate psychosocial and family-oriented interventions in genetic counselling, addressing the holistic experience of hereditary disease. Recommendations for enhancing the services available are provided. The multi-family discussion group, combining educative and supportive services with a family focus, can be successfully adapted in genetic counselling protocols.

Mitochondrial content reflects oocyte variability and fertilization outcome.

OBJECTIVE: To determine the content of mitochondrial DNA (mtDNA) in oocytes from a range of patients with fertilization success and failure. DESIGN: Analysis of mtDNA content in fertilized and unfertilized oocytes and embryos by real-time polymerase chain reaction (PCR). SETTING: University hospital infertility and research center. PATIENT(S): Fifty-four women seeking treatment for infertility. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): A total of 142 fertilized and unfertilized oocytes were classified into three main groups. Group I consisted of 35 fertilized oocytes from 21 patients; group II, 65 unfertilized oocytes from 36 patients; and group III, 42 degenerate oocytes from 23 patients. Mitochondrial DNA content was determined by SYBR Green real-time PCR-based assay. RESULT(S): The mean mtDNA copy number for the fertilized oocytes was 250,454, whereas for the unfertilized group it was 163,698. There were significant differences for mtDNA copy number between the male factor and female factor infertility unfertilized oocytes and between the unexplained infertility and female factor infertility groups. The mean copy number for the degenerate oocyte group was 44,629, which was significantly different from the other subdivisions in this group. CONCLUSION(S): Mitochondrial DNA content is critical to fertilization outcome and serves as an important marker of oocyte quality, explaining some cases of fertilization failure.

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