Hereditary diffuse gastric cancer: updated clinical practice guidelines

Blair, Vanessa; McLeod, Maybelle; Carneiro, Fátima; Coit, Daniel G.; D'Addario, Johanna L.; Dieren, Jolanda M. van; Harris, Kirsty L.; Hoogerbrugge, Nicoline; Oliveira, Carla; Post, Rachel S. van der; Arnold, Julie; Benusiglio, Patrick R.; Bisseling, Tanya M.; Boussioutas, Alex; Cats, Annemieke; Charlton, Amanda; Schreiber, Karen E. Chelcun; Davis, Jeremy L.; Pietro, Massimiliano di; Fitzgerald, Rebecca C.; Ford, James M.; Gamet, Kimberley; Gullo, Irene; Hardwick, Richard; Huntsman, David G.; Kaurah, Pardeep; Kupfer, Sonia S.; Latchford, Andrew; Mansfield, Paul F.; Nakajima, Takeshi; Parry, Susan; Rossaak, Jeremy; Sugimura, Haruhiko; Svrcek, Magali; Tischkowitz, Marc; Ushijima, Toshikazu; Yamada, Hidetaka; Yang, Han Kwang; Claydon, Adrian; Figueiredo, Joana; Paringatai, Karyn; Seruca, Raquel; Bougen-Zhukov, Nicola; Brew, Tom P.; Busija, Simone; Carneiro, Patrı́cia; DeGregorio, Lynn; Fisher, Helen C.; Gardner, Erin R.; Godwin, Tanis; Holm, Katharine Nichole; Humar, Bostjan; Lintott, Caroline J.; Monroe, Elizabeth C.; Müller, M.; Norero, Enrique; Nouri, Yasmin; Paredes, Joana; Sanches, J. Miguel; Schulpen, Emily; Ribeiro, Ana Sofia; Sporle, Andrew; Whitworth, James; Zhang, Liying; Reeve, Anthony E.; Guilford, Parry

doi:10.1016/s1470-2045(20)30219-9

Cited by 264 publications

(452 citation statements)

References 63 publications

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“…Also, all Māori with DGC, 8 families with DGC and cleft lip/palate 9 and individuals with HDGC precursor lesions 10 should be tested for CDH1 and CTNNA1 mutations. For full details of the 2020 HDGC genetic testing criteria (Table 1), see the recently updated HGDC guidelines publication 3 …”

Section: Hdgcmentioning

confidence: 99%

“…These superficial SRCCs show very indolent behaviour. Confirmed HDGC patients who choose to undergo surveillance endoscopy instead of PTG should therefore be especially screened for large, numerous or advanced DGC 3 . This may warrant prompt total gastrectomy.…”

Section: Hdgcmentioning

confidence: 99%

“…Asymptomatic carriers are advised to undergo annual gastroscopy, and prophylactic gastrectomy can be considered. Annual endoscopic gastroscopy is also recommended for HDGC‐like families and families with a ‘ CDH1 variant of unknown significance’ for at least 2 years; after 2 years, the interval may be increased 3 …”

Section: Hdgcmentioning

confidence: 99%

“…In contrast, when the entire gastric mucosa is not examined, HDGC is found in only 62.5% of total gastrectomy specimens. Accordingly, the total‐embedding protocol and thorough histopathological examination of the entire gastric mucosa are considered to constitute the gold standard practice for the evaluation of total gastrectomy specimens from CDH1 carriers 3,25 . However, for routine histopathology laboratories with constrained resources, total examination of the gastric mucosa may not be feasible.…”

Section: Hdgcmentioning

confidence: 99%

“…This article reviews the essential clinical and histopathological features of the aforementioned syndromes, describing the most recent advances in their diagnosis. In particular, the focus of this article is HDGC, in light of the updated clinical practice guidelines 3 and emerging concepts regarding the morphology of HDGC.…”

Section: Introductionmentioning

confidence: 99%

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Recent advances in the pathology of heritable gastric cancer syndromes

2020

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Despite the relative rarity of hereditary gastric cancer syndromes, the prompt recognition of their specific clinical features and histopathological characteristics is pivotal in offering patients the most appropriate treatment. In this article, we address the three major inherited syndromes that primarily affect the stomach: hereditary diffuse gastric cancer (HDGC), caused by germline variants in CDH1 and CTNNA1; gastric adenocarcinoma and proximal polyposis of the stomach, caused by germline mutations in promoter 1B of APC; and familial intestinal gastric cancer, which has a poorly defined genetic cause. The main focus will be on HDGC, in light of the recent publication of updated clinical practice guidelines and emerging concepts regarding HDGC histopathology. In particular, we describe the broad morphological spectrum of HDGC lesions, stressing the importance of recognising indolent and aggressive phenotypes. Moreover, we discuss the increased risk of gastric (pre)malignancies developing in patients with other well‐defined hereditary cancer syndromes, such as familial adenomatous polyposis, Lynch syndrome, Peutz–Jeghers syndrome, juvenile polyposis, Li–Fraumeni syndrome, and hereditary breast and ovarian cancer syndrome.

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Section: Hdgcmentioning

confidence: 99%

Section: Hdgcmentioning

confidence: 99%

Section: Hdgcmentioning

confidence: 99%

Section: Hdgcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Recent advances in the pathology of heritable gastric cancer syndromes

2020

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Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer

et al. 2022

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ImportanceThe E-cadherin gene, CDH1, and the α-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown.ObjectiveTo assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC.Design, Setting, and ParticipantsThis cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020.Main Outcomes and MeasuresIncidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC.ResultsAmong 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (&gt;10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC.Conclusions and RelevanceThis study provided a genetic landscape for HDGC. The study’s findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.

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CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype

Corso,

Marino,

Zanzottera

et al. 2024

JAMA Netw Open

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ImportancePathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation.ObjectivesTo evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers’ tumor samples, and the association of genetic profiles with clinical-pathological data and survival.Design, Setting, and ParticipantsThis single-center, longitudinal, prospective cohort study was conducted from January 1, 1997, to December 31, 2021, with follow-up until January 31, 2023. Women with LBC seen at the European Institute of Oncology were included. Testing for germline CDH1, BRCA1, and BRCA2 genes was performed. Somatic profiling was assessed for germline CDH1 carriers.Main Outcomes and MeasuresAccurate estimates of prevalence of germline CDH1 variants among patients with HLBC and the association of somatic sequence alteration with HLBC syndrome. The Kaplan-Meier method and a multivariable Cox proportional hazards regression model were applied for overall and disease-free survival analysis.ResultsOf 5429 cases of primary LBC, familial LBC phenotype accounted for 1867 (34.4%). A total of 394 women with LBC were tested, among whom 15 germline CDH1 variants in 15 unrelated families were identified. Among these variants, 6 (40.0%) were P/LP, with an overall frequency of 1.5% (6 of 394). Of the 6 probands with P/LP CDH1 LBC, 5 (83.3%) had a positive family history of BC and only 1 (16.7%) had sporadic juvenile early-onset LBC. No germline BRCA1 and BRCA2 variants were identified in CDH1 carriers. An inactivating CDH1 mechanism (second hit) was identified in 4 of 6 explored matched tumor samples (66.7%) in P/LP germline carriers. The P/LP CDH1 LBC variant carriers had a significantly lower age at diagnosis compared with the group carrying CDH1 variants of unknown significance or likely benign (42.5 [IQR, 38.3-43.0] vs 51.0 [IQR, 45.0-53.0] years; P = .03).Conclusions and RelevanceIn this cohort study, P/LP germline CDH1 variants were identified in individuals not fulfilling the classic clinical criteria for HDGC screening, suggesting that identification of these variants may provide a novel method to test women with LBC with early age at diagnosis and/or positive family history of BC.

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Hereditary diffuse gastric cancer: updated clinical practice guidelines

Cited by 264 publications

References 63 publications

Recent advances in the pathology of heritable gastric cancer syndromes

Recent advances in the pathology of heritable gastric cancer syndromes

Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer

CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype

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