Simplified and more sensitive criteria for identifying individuals with pathogenicCDH1variants

Abstract

BackgroundHereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome most often caused by pathogenic variants in CDH1. The International Gastric Cancer Linkage Consortium (IGCLC) recently updated its criteria for genetic testing. The purpose of this study was to estimate the sensitivity of IGCLC’s 2020 criteria for identifying carriers of CDH1 pathogenic variants and to formulate a new set of criteria that is simpler and more sensitive.MethodsMedical histories of 112 CDH1 mutation carriers, identified predominantly by multigene panel testing, and their 649 family members were reviewed. The percentage of subjects fulfilling the IGCLC 2015 and 2020 criteria was calculated, once without making any assumptions about unavailable pathology, and once assuming gastric cancer to be diffuse when pathology was unavailable. For comparison, we calculated the percentage of subjects who fulfilled our proposed criteria.ResultsWhen making no assumptions about missing pathology, a small (19%) and equal percentage of CDH1 mutation carriers fulfilled the IGCLC 2015 and 2020 criteria. When assuming unspecified gastric cancer to be diffuse, 45 out of 112 (40%) subjects met the 2015 criteria and 53 out of 112 (47%) met the 2020 criteria. Eighty-seven per cent (97/112) fulfilled our proposed criteria.ConclusionIn consecutive cases, mostly unselected for clinical criteria of HDGC, the IGCLC 2020 criteria are, at best, marginally more sensitive than previous iterations, but they are also more cumbersome. Unavailable cancer pathology reports are a real-world obstacle to their proper application. Our proposed Yale criteria both address this issue and offer significantly greater sensitivity than the IGCLC 2020 criteria.

Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes

“…The lobular breast cancer-expanded set of criteria showed better performance than the 2020 HDGC criteria (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004), as well as better specificity (0·90 [95% CI 0·88–0·93] vs 0·34 [0·30–0·37]), and superiority in true negative detection (p<0·0001) compared with the Yale criteria 16 (specificity 0·34 [95% CI 0·30–0·37]; figure 5B, C ; appendix pp 70–72 ), and equivalent true negative detection to that of the 2015 and 2020 HDGC criteria (p=0·059 and p=0·21, respectively; figure 5C ). The lobular breast cancer-expanded criteria also showed better sensitivity (0·94 [95% CI 0·89–0·97]) than the 2015 HDGC criteria (0·77 [0·70-0·83] and the 2020 HDGC criteria (0·84 [0·77–0·89]), with superior true positive detection (p<0·0001 and p=0·0025, respectively), while maintaining high specificity ( figure 5C ; appendix pp 70–72 ).…”

“…Family history was revisited and compliance with the 2015 criteria, 1 2020 criteria, 2 or Yale criteria 16 for HDGC ( appendix pp 5–46 ) was registered. For the purpose of comparative analysis, a family with HDGC was defined as any family fulfilling the 2015 clinical criteria for HDGC.…”

“… 12 , 14 Additionally, a 2022 cohort study of patients with cancer showed that CDH1 germline pathogenic or likely pathogenic variants are enriched in patients with diffuse gastric cancer and lobular breast cancer. 15 The high number of patients with breast cancer carrying CDH1 pathogenic or likely pathogenic variants in the USA led Lerner and colleagues 16 to propose the use of clinical criteria for hereditary breast and ovarian cancer, in addition to the modified and less restrictive 2020 criteria for HDGC (also known as Yale criteria), to select patients for CDH1 testing. Although this approach increased the sensitivity of the criteria, no data were provided regarding their specificity or positive predictive value.…”

“…Although this approach increased the sensitivity of the criteria, no data were provided regarding their specificity or positive predictive value. 16 …”

Pleiotropic cancer manifestations of germline CDH1 mutations: Risks and management

“…Although some Authors stress to perform PTG also in germline CDH1 pathogenic mutation carriers with unclear family history for GC, 30 PTG should be considered only in case of a clear HDGC phenotype with a documented germline CDH1 pathogenic variant. Individuals with variants of unknown significance (VUS), and without a clear family history of GC are not eligible for PTG 4,31 …”