Fillman Corrine, Anantharajah Arravinth, Marmelstein Briana, Dillon Monica, Horton Carolyn, Peterson Candace, Lopez Joseph, Tondon Rashmi, Brannan Terra, Katona Bryson W
Cancer Risk and Genetics Program, St. Luke's University Health Network, Bethlehem, PA, USA.
University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Fam Cancer. 2023 Oct;22(4):521-526. doi: 10.1007/s10689-023-00346-z. Epub 2023 Aug 4.
Pathogenic germline variants (PGVs) in the CDH1 gene are associated with diffuse gastric and lobular breast cancer syndrome (DGLBC) and can increase the lifetime risk for both diffuse gastric cancer and lobular breast cancer. Given the risk for diffuse gastric cancer among individuals with CDH1 PGVs is up to 30-40%, prophylactic total gastrectomy is often recommended to affected individuals. Therefore, accurate interpretation of CDH1 variants is of the utmost importance for proper clinical decision-making. Herein we present a 45-year-old female, with lobular breast cancer and a father with gastric cancer of unknown pathology at age 48, who was identified to have an intronic variant of uncertain significance in the CDH1 gene, specifically c.833-9 C > G. Although the proband did not meet the International Gastric Cancer Linkage Consortium (IGCLC) criteria for gastric surveillance, she elected to pursue an upper endoscopy where non-targeted gastric biopsies identified a focus of signet ring cell carcinoma (SRCC). The proband then underwent a total gastrectomy, revealing numerous SRCC foci, but no invasive diffuse gastric cancer. Simultaneously, a genetic testing laboratory performed RNA sequencing to further analyze the CDH1 intronic variant, identifying an abnormal transcript from a novel acceptor splice site. The RNA analysis in conjunction with the patient's gastric foci of SRCC and family history was sufficient evidence for reclassification of the variant from uncertain significance to likely pathogenic. In conclusion, we report the first case of the CDH1 c.833-9 C > G intronic variant being associated with DGLBC and illustrate how collaboration among clinicians, laboratory personnel, and patients is crucial for variant resolution.
CDH1基因中的致病性种系变异（PGV）与弥漫性胃癌和小叶性乳腺癌综合征（DGLBC）相关，可增加弥漫性胃癌和小叶性乳腺癌的终生风险。鉴于携带CDH1 PGV的个体患弥漫性胃癌的风险高达30%-40%，通常建议受影响个体进行预防性全胃切除术。因此，准确解读CDH1变异对于正确的临床决策至关重要。在此，我们报告一名45岁女性，患有小叶性乳腺癌，其父亲在48岁时患有病理不明的胃癌，该女性被确定在CDH1基因中有一个意义未明的内含子变异，具体为c.833-9 C＞G。尽管先证者不符合国际胃癌连锁联盟（IGCLC）的胃癌监测标准，但她选择接受上消化道内镜检查，非靶向胃活检发现了印戒细胞癌（SRCC）病灶。先证者随后接受了全胃切除术，发现了许多SRCC病灶，但未发现侵袭性弥漫性胃癌。同时，一家基因检测实验室进行了RNA测序，以进一步分析CDH1内含子变异，从一个新的受体剪接位点鉴定出一个异常转录本。RNA分析结合患者的胃SRCC病灶和家族史，足以作为将该变异从意义未明重新分类为可能致病的证据。总之，我们报告了首例CDH1 c.833-9 C＞G内含子变异与DGLBC相关的病例，并说明了临床医生、实验室人员和患者之间的合作对于变异解析的关键作用。
