First estimates of diffuse gastric cancer risks for carriers of<i>CTNNA1</i>germline pathogenic variants

Coudert, Marie; Drouet, Youenn; Delhomelle, Hélène; Svrcek, Magali; Benusiglio, Patrick R.; Coulet, Florence; Clark, Donald W.; Katona, Bryson W.; Hest, Liselotte P. van; Kolk, Lizet E. van der; Cats, Annemieke; Dieren, Jolanda M. van; Nehoray, Bita; Slavin, Thomas P.; Spier, Isabel; Hüneburg, Robert; Lobo, Silvana; Oliveíra, Carla; Boussemart, Lise; Masson, Laure; Chiésa, Jean; Schwartz, Mathias; Bruno, Benedetto; Golmard, Lisa; Bouvier, Anne–Marie; Bonadona, Valérie; Stoppa‐Lyonnet, Dominique; Lasset, Christine; Colas, Chrystelle

doi:10.1136/jmg-2022-108740

Cited by 12 publications

(8 citation statements)

References 19 publications

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“…For CDH1 carriers, early estimates of DGC risk were as high as 83 per cent by 80 years of age 132 ; however, more recent data, ascertained with less bias toward gastric cancer predominant families, have shown gastric cancer risks of 33–42 per cent by 80 years of age 110 , 111 . The first risk estimate in CTNNA1 carriers was also recently reported showing a DGC risk by 80 years of age of 49–57 per cent 112 , yet only included families with DGC. Therefore, the quoted lifetime gastric cancer risk in CTNNA1 carriers will also likely decrease as more families are identified.…”

Section: Hereditary Gastric Cancermentioning

confidence: 99%

Hereditary colorectal, gastric, and pancreatic cancer: comprehensive review

2023

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Background Inheritance patterns show familial clustering of gastrointestinal cancers, and multiple germline conditions have now been identified that predispose to colorectal, gastric, and pancreatic cancers. Methods A narrative review based on recent relevant literature was conducted. Results Lynch syndrome, formerly known as hereditary non-polyposis colorectal cancer, increases the risk of several abdominal cancers, with the highest population prevalence. Familial adenomatous polyposis and some of the more infrequent polyposis syndromes have distinct characteristics affecting various organ-specific cancer risks. Hereditary gastric and pancreatic cancer syndromes include those also causing colorectal cancer, while additional genetic disorders predisposing only to upper gastrointestinal malignancies have been recognized more recently. Diagnosing and managing hereditary cancer syndromes requires multidisciplinary expertise and may be best managed in tertiary centres, with a need to consider patient preference and ensure shared decision-making. Conclusion Several germline conditions predispose to colorectal, gastric, and pancreatic cancer, which inform identification, surveillance regimens, prevention, cascade screening, counselling, and surgical management. The authors describe developments in the hereditary origin of colorectal, gastric, and pancreatic cancer with current recommendations in surveillance and surgical management.

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Section: Hereditary Gastric Cancermentioning

confidence: 99%

Hereditary colorectal, gastric, and pancreatic cancer: comprehensive review

2023

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“…A number of hereditary cancer predisposition syndromes are associated with elevated risk of GC, which has led to a multitude of syndrome-specific guidelines for GC surveillance [ 77 ]. Patients with hereditary diffuse gastric cancer syndrome (HDGC) due to a PV in CDH1 or CTNNA1 have the highest lifetime cumulative risk of GC [ 57 , 78 , 79 ]. In HDGC, if gastrectomy is declined or delayed, guidelines recommend annual upper endoscopy with targeted and non-targeted gastric biopsies [ 78 ].…”

Section: Gastric Surveillance Considerations In Brca1/2 ...mentioning

confidence: 99%

Gastric Cancer Risk and Pathogenesis in BRCA1 and BRCA2 Carriers

Buckley

Niccum

Maxwell

et al. 2022

Cancers

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Carriers of a pathogenic germline variant (PV) in BRCA1 or BRCA2 are at increased risk for a number of malignancies, including breast, ovarian, pancreatic, and prostate cancer. In this review, we discuss emerging evidence that BRCA2 PV carriers, and likely also BRCA1 PV carriers, are also at increased risk for gastric cancer (GC), highlighting that GC may be part of the BRCA1/2 cancer risk spectrum. While the pathogenesis of GC among BRCA1/2 PV carriers remains unclear, increasing evidence reveals that GCs are often enriched with mutations in homologous recombination-associated genes such as BRCA1/2, and that GC prognosis and response to certain therapies can depend on BRCA1/2 expression. Given the strength of data published to date, a risk management strategy for GC among BRCA1/2 PV carriers is needed, and herein we also propose a potential strategy for GC risk management in this population. Moving forward, further study is clearly warranted to define the mechanistic relationship between BRCA1/2 PVs and development of GC as well as to determine how GC risk management should be factored into the clinical care of BRCA1/2 carriers.

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“…Until recently, CDH1 was the only known susceptibility gene involved in HDGC, but, in 2013, Majewski and collaborators described a germline variant in the catenin alpha-1 gene (CTNNA1) for the first time in a family that fulfilled the HDGC clinical criteria [3]. Since then, to our knowledge, 13 pathogenic variants in CTNNA1 have been described in 15 families fulfilling the HDGC criteria [3][4][5][6][7][8][9][10][11]. Additionally, loss-of-function variants have been described in families without HDGC clinical criteria [9,11].…”

Section: Introductionmentioning

confidence: 99%

“…Benusiglio and collaborators reported two asymptomatic CTNNA1 pathogenic variant carriers, who displayed DGC foci in the prophylactic gastrectomy and intramucosal focus on esophagogastroduodenoscopy specimens, with loss of catenin alpha-1 expression, suggesting that pathogenic variants in CDH1 and CTNNA1 may have similar implications in DGC risk [1,7]. The penetrance of pathogenic CTNNA1 variants is still unclear, although Coudert and collaborators have recently published the first penetrance estimate for DGC in CTNNA1 families as 49-57% at 80 years [10]. The association of CTNNA1 pathogenic variants with increased LBC risk is also still inconclusive; although some studies have been associating CTNNA1 and breast cancer [9,[12][13][14], this association remains to be clarified since the subtype of these cancers was not specified.…”

Section: Introductionmentioning

confidence: 99%

Frequency of CDH1, CTNNA1 and CTNND1 Germline Variants in Families with Diffuse and Mixed Gastric Cancer

Guerra,

Pinto,

Pinto

et al. 2023

Cancers

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The most well-characterized hereditary form of gastric cancer is hereditary diffuse gastric cancer (HDGC), an autosomal dominant syndrome characterized by an increased risk of diffuse gastric and lobular breast cancer. HDGC is predominantly caused by germline pathogenic variants in the CDH1 gene, and more rarely in the CTNNA1 gene. Furthermore, the International Gastric Cancer Linkage Consortium (IGCLC) guidelines do not clarify whether or not mixed gastric cancer (with a diffuse component) should be considered in the HDGC genetic testing criteria. We aimed to evaluate the contribution of CTNNA1 and CTNND1 germline variants to HDGC. Additionally, we also intended to compare the frequencies of CDH1 and CTNNA1 (and eventually CTNND1) germline variants between patients with diffuse and mixed gastric carcinomas to evaluate if genetic testing for these genes should or should not be considered in patients with the latter. We analyzed the CDH1 gene in 67 cases affected with early-onset/familial mixed gastric carcinomas and the CTNNA1 and CTNND1 genes in 208 cases with diffuse or mixed gastric cancer who had tested negative for CDH1 pathogenic germline variants. A deleterious CTNNA1 germline variant was found in 0.7% (1/141) of diffuse gastric cancer patients meeting the 2020 IGCLC criteria, as compared to the rate of 2.8% of CDH1 deleterious variants found by us in this setting. No deleterious variants were found in CTNND1, but six variants of uncertain significance were identified in this gene. We did not find any pathogenic CDH1, CTNNA1 or CTNND1 variant in index patients with early-onset/familial mixed gastric cancer, so there is no evidence that supports including this tumor type in the testing criteria for germline variants in these genes. The role of the CTNND1 gene in inherited gastric cancer predisposition is still unclear.

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First estimates of diffuse gastric cancer risks for carriers ofCTNNA1germline pathogenic variants

Cited by 12 publications

References 19 publications

Hereditary colorectal, gastric, and pancreatic cancer: comprehensive review

Hereditary colorectal, gastric, and pancreatic cancer: comprehensive review

Gastric Cancer Risk and Pathogenesis in BRCA1 and BRCA2 Carriers

Frequency of CDH1, CTNNA1 and CTNND1 Germline Variants in Families with Diffuse and Mixed Gastric Cancer

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