JAMA oncology · 2015
Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.
СтатьяМногоцентровое исследованиеVideo-Audio MediaНазвание и аннотация: Перевод в очереди
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Hansford Samantha, Kaurah Pardeep, Li-Chang Hector, Woo Michelle, Senz Janine, Pinheiro Hugo, Schrader Kasmintan A, Schaeffer David F, Shumansky Karey, Zogopoulos George, Santos Teresa Almeida, Claro Isabel, Carvalho Joana, Nielsen Cydney, Padilla Sarah, Lum Amy, Talhouk Aline, Baker-Lange Katie, Richardson Sue, Lewis Ivy, Lindor Noralane M, Pennell Erin, MacMillan Andree, Fernandez Bridget, Keller Gisella, Lynch Henry, Shah Sohrab P, Guilford Parry, Gallinger Steven, Corso Giovanni, Roviello Franco, Caldas Carlos, Oliveira Carla, Pharoah Paul D P, Huntsman David G
Аннотация
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.
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.
Предметные рубрики MeSH
AdultAge DistributionAge FactorsAgedAged, 80 and overAntigens, CDBiomarkers, TumorBreast NeoplasmsCadherinsCanadaDNA Mutational AnalysisEuropeFemaleGenetic Predisposition to DiseaseGerm-Line MutationHeredityHumansIncidenceMaleMiddle AgedPedigreePenetrancePhenotypePredictive Value of TestsRisk AssessmentRisk FactorsSex DistributionSex FactorsStomach NeoplasmsYoung Adult