遗传性乳腺小叶癌患者的胃癌风险
遗传性乳腺小叶癌已被认为是一种独立的癌症综合征，发生于种系抑癌基因CDH1致病或可能致病变异且无胃癌家族史的家族，而CDH1功能丧失变异已知通常可以导致遗传性弥漫型胃癌综合征，其中包括乳腺小叶癌风险升高。遗传性弥漫型胃癌综合征患者发生胃癌的终生风险高达33%～42%，发生乳腺癌的终生风险高达43%～55%。由于遗传性弥漫型胃癌的侵袭性生物学特性且缺乏有效监测方法，故建议对CDH1变异携带者进行降低风险全胃切除术。虽然隐匿型印戒细胞癌常见于遗传性弥漫型胃癌患者，但是遗传性乳腺小叶癌患者发生胃癌的风险尚不明确。种系基因变异与癌症家族史相比，更有可能提示遗传性癌症风险。那么，CDH1变异所致遗传性乳腺小叶癌对胃癌发病风险的影响如何？
2021年10月13日，《美国医学会杂志》外科学分册在线发表美国国家癌症研究所的研究报告，通过确定无症状者的印戒细胞癌发病率，对CDH1种系功能丧失变异所致遗传性乳腺小叶癌患者的隐匿型胃癌发病风险进行了调查分析。
该前瞻定群研究于2017年10月～2021年1月从一家四级医学中心（美国国家癌症研究所）入组种系CDH1致病或可能致病变异患者283例，其中女性199例（70.3%）、白人259例（91.5%），年龄18～81岁（中位48岁），来自151个家族。
数据分析于2021年5月进行，主要研究终点为遗传性乳腺小叶癌患者的隐匿型印戒细胞胃癌发病率。通过皮尔逊卡方检验比较分类因素对隐匿型印戒细胞胃癌发病率的影响，包括个人和家族病史、来自降低风险全胃切除术和内窥镜监测的基因型和病理学数据。
结果，根据乳腺癌和/或胃癌家族史对患者进行分类：
家族史有乳腺癌无胃癌的遗传性乳腺小叶癌患者：44例（15.5%）
家族史有胃癌无乳腺癌的遗传性弥漫型胃癌患者：46例（16.2%）
家族史有乳腺癌和胃癌的遗传性乳腺小叶癌和遗传性弥漫型胃癌混合患者：193例（68.2%）
遗传性乳腺小叶癌患者来自31个不同的家族，携带19种CDH1变异；其中10种变异（52.6%）也存在于遗传性弥漫型胃癌患者和混合患者。
几乎全部（93.8%）由于CDH1致病或可能致病变异而选择降低风险全胃切除术的遗传性乳腺小叶癌患者最终病理学检查发现隐匿型印戒细胞胃腺癌（年龄21～67岁，中位50岁）。遗传性弥漫型胃癌无症状患者的隐匿型印戒细胞胃腺癌发病率相似（94.7%，P=0.98）。
因此，该单中心小样本前瞻研究结果表明，无胃癌家族史的CDH1致病或可能致病变异携带者，隐匿型印戒细胞胃癌发病率较高。无论家族史如何，种系CDH1致病或可能致病变异都极有可能表现为胃癌。这些数据如果被多中心大样本前瞻研究证实，将有助于为可能发生遗传性乳腺小叶癌的CDH1变异家族提供遗传咨询。对于遗传性乳腺小叶癌患者，胃癌风险评定和遗传咨询应该根据种系CDH1变异提供信息，而与癌症家族史无关。
JAMA Surg. 2021 Oct 13. Online ahead of print.
Association Between Hereditary Lobular Breast Cancer Due to CDH1 Variants and Gastric Cancer Risk.
Gamble LA, Rossi A, Fasaye GA, Kesserwan C, Hernandez JM, Blakely AM, Davis JL.
National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
This cohort study assess gastric cancer risk among patients who received a diagnosis of hereditary lobular breast cancer owing to a germline loss-of-function variant in CDH1 by establishing prevalence of signet ring cell carcinomas among asymptomatic patients.
QUESTION: Is there an association between hereditary lobular breast cancer due to CDH1 variants and gastric cancer risk?
FINDINGS: In this cohort study of 283 patients with hereditary lobular breast cancer due to CDH1 pathogenic or likely pathogenic variants, a high prevalence of occult signet ring cell gastric cancer was found.
MEANING: Gastric cancer risk assessment and counseling for patients with hereditary lobular breast cancer should be informed by germline CDH1 variants irrespective of family history of cancer.
IMPORTANCE: Hereditary cancer risk is informed by the presence of a germline gene variant more so than by family history of cancer.
OBJECTIVE: To assess gastric cancer risk among patients who received a diagnosis of hereditary lobular breast cancer (HLBC) owing to a germline loss-of-function variant in CDH1 by establishing prevalence of signet ring cell carcinomas among asymptomatic patients.
DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of patients with germline CDH1 pathogenic or likely pathogenic (P/LP) variants at a quaternary medical center were enrolled between October 2017 and January 2021. Data analysis was performed in May 2021. Analyses for associations were performed for these 3 patient groups: (1) family history of breast cancer and no gastric cancer in the HLBC group; (2) family history of gastric cancer and no breast cancer in the hereditary diffuse gastric cancer (HDGC) group; and (3) family history of both breast and gastric cancers in the mixed group. Categorical variables were compared using the Pearson χ2 test.
MAIN OUTCOMES AND MEASURES: The primary end point of this study was the prevalence of occult signet ring cell carcinoma of the stomach in patients with HLBC. Personal and family medical history, genotype, and pathologic data from risk-reducing total gastrectomy and surveillance endoscopy were examined.
RESULTS: A total of 283 patients with CDH1 P/LP variants (199 [70.3%] were female, and 259 [91.5%] were White; median age, 48 years [range, 18-81 years]) were enrolled in a prospective study of HDGC. The cohort consisted of 151 families. Patients were categorized according to family history of breast and/or gastric cancer: HLBC 15.5% [44 of 283 patients]), HDGC (16.2% [46 of 283 patients]), and mixed (68.2% [193 of 283 patients]). The HLBC group included 31 distinct families with 19 CDH1 variants; 10 of those variants were also present in the HDGC and mixed groups (52.6% [10 of 19 variants]). Nearly all of the patients with HLBC (93.8% [15 of 16 variants]) who elected for risk-reducing total gastrectomy owing to their underlying CDH1 P/LP variant harbored occult signet ring cell gastric adenocarcinoma on final pathology (median age, 50 years [range, 21-67 years]). The prevalence of occult gastric cancer among asymptomatic patients in the HDGC group was similar (94.7% [18 of 19 of variants]; P = .98).
CONCLUSIONS AND RELEVANCE: Carriers of CDH1 P/LP variants with no family history of gastric cancer exhibited high rates of occult signet ring cell gastric cancer. Germline CDH1 P/LP variants appear to have a highly penetrant gastric phenotype irrespective of family history. These data may prove useful for counseling families with CDH1 variants presumed to have HLBC.
PMID: 34643667
DOI: 10.1001/jamasurg.2021.5118