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Abstract：
BACKGROUND: Multiple primary malignancies are rare in cancer patients, and risk factors may include genetics, viral infection, smoking, radiation, and other environmental factors. Lynch syndrome (LS) is the most prevalent form of hereditary predisposition to double primary colorectal and endometrial cancer in females. LS, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a common autosomal dominant condition. Pathogenic germline variants in the DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2, and less frequently, deletions in the 3\' end of EPCAM cause LS. It manifested itself as loss of MMR nuclear tumor staining (MMR protein deficient, dMMR).
METHODS: This case study describes a double primary carcinoma in a 49-year-old female. In June 2022, the patient was diagnosed with highly to moderately differentiated endometrioid adenocarcinoma. The patient\'s mother died of esophageal cancer at age 50, and the father died of undefined reasons at age 70. Immunohistochemical stainings found ER (++), PR (++), P53 (+), MSH2 (-), MSH6 (+), MLH1 (+), and PMS2 (+). MMR gene sequencing was performed on endometrial tumor and peripheral blood samples from this patient. The patient carried two pathogenic somatic mutations in the endometrial tumor, MSH6 c.3261dupC (p.Phe1088LeufsTer5) and MSH2 c.445_448dup (p.Val150fs), in addition to a rare germline mutation MSH6 c.133G > C (p.Gly45Arg). Two years ago, the patient was diagnosed with moderately differentiated adenocarcinoma in the left-half colon. Immunohistochemical stainings found MSH2(-), MSH6(+), MLH1(+), and PMS2(+) (data not shown).
CONCLUSIONS: In the case of a patient with double primary EC and CRC, a careful evaluation of the IHC and the genetic data was presented. The patient carried rare compound heterozygous variants, a germline missense mutation, and a somatic frameshift mutation of MSH6, combined with a novel somatic null variant of MSH2. Our study broadened the variant spectrum of double primary cancer and provided insight into the molecular basis for abnormal MSH2 protein loss and double primary carcinoma.
METHODS: This case study describes a double primary carcinoma in a 49-year-old female. In June 2022, the patient was diagnosed with highly to moderately differentiated endometrioid adenocarcinoma. The patient\'s mother died of esophageal cancer at age 50, and the father died of undefined reasons at age 70. Immunohistochemical stainings found ER (++), PR (++), P53 (+), MSH2 (-), MSH6 (+), MLH1 (+), and PMS2 (+). MMR gene sequencing was performed on endometrial tumor and peripheral blood samples from this patient. The patient carried two pathogenic somatic mutations in the endometrial tumor, MSH6 c.3261dupC (p.Phe1088LeufsTer5) and MSH2 c.445_448dup (p.Val150fs), in addition to a rare germline mutation MSH6 c.133G > C (p.Gly45Arg). Two years ago, the patient was diagnosed with moderately differentiated adenocarcinoma in the left-half colon. Immunohistochemical stainings found MSH2(-), MSH6(+), MLH1(+), and PMS2(+) (data not shown).
CONCLUSIONS: In the case of a patient with double primary EC and CRC, a careful evaluation of the IHC and the genetic data was presented. The patient carried rare compound heterozygous variants, a germline missense mutation, and a somatic frameshift mutation of MSH6, combined with a novel somatic null variant of MSH2. Our study broadened the variant spectrum of double primary cancer and provided insight into the molecular basis for abnormal MSH2 protein loss and double primary carcinoma.
摘要：
背景：多发性原发性恶性肿瘤在癌症患者中很少见，风险因素可能包括遗传学，病毒感染,吸烟,辐射,和其他环境因素。Lynch综合征（LS）是女性双原发性结直肠癌和子宫内膜癌的最普遍的遗传易感性形式。LS,也称为遗传性非息肉病性结直肠癌（HNPCC），是一种常见的常染色体显性条件。DNA错配修复（MMR）基因中的致病性种系变异，即MLH1、MSH2、MSH6和PMS2，频率较低，在EPCAM的3'端删除导致LS。它表现为MMR核瘤染色丢失（MMR蛋白缺陷，dMMR)。
方法：本案例研究描述了一名49岁女性的双原发癌。2022年6月，患者被诊断为高分化至中分化子宫内膜样腺癌。患者的母亲在50岁时死于食道癌，父亲在70岁时死于不明原因。免疫组织化学染色发现ER（++），PR(++),P53(+),MSH2(-),MSH6(+),MLH1(+),和PMS2(+)。对该患者的子宫内膜肿瘤和外周血样本进行MMR基因测序。该患者在子宫内膜肿瘤中携带两个致病性体细胞突变，MSH6c.3261dupC（p。Phe1088LeufsTer5）和MSH2c.445_448dup（p。Val150fs),除了罕见的种系突变MSH6c.133G>C（p。Gly45Arg）。两年前,患者被诊断为左半结肠中分化腺癌.免疫组织化学染色发现MSH2（-），MSH6(+),MLH1(+),和PMS2(+)(数据未显示)。
结论：对于患有双原发性EC和CRC的患者，我们提供了对IHC和遗传数据的仔细评估。患者携带罕见的复合杂合变异体,种系错义突变,和MSH6的体细胞移码突变，以及MSH2的新型体细胞无效变体。我们的研究拓宽了双原发癌的变异谱，并为MSH2蛋白异常丢失和双原发癌的分子基础提供了见解。
方法：本案例研究描述了一名49岁女性的双原发癌。2022年6月，患者被诊断为高分化至中分化子宫内膜样腺癌。患者的母亲在50岁时死于食道癌，父亲在70岁时死于不明原因。免疫组织化学染色发现ER（++），PR(++),P53(+),MSH2(-),MSH6(+),MLH1(+),和PMS2(+)。对该患者的子宫内膜肿瘤和外周血样本进行MMR基因测序。该患者在子宫内膜肿瘤中携带两个致病性体细胞突变，MSH6c.3261dupC（p。Phe1088LeufsTer5）和MSH2c.445_448dup（p。Val150fs),除了罕见的种系突变MSH6c.133G>C（p。Gly45Arg）。两年前,患者被诊断为左半结肠中分化腺癌.免疫组织化学染色发现MSH2（-），MSH6(+),MLH1(+),和PMS2(+)(数据未显示)。
结论：对于患有双原发性EC和CRC的患者，我们提供了对IHC和遗传数据的仔细评估。患者携带罕见的复合杂合变异体,种系错义突变,和MSH6的体细胞移码突变，以及MSH2的新型体细胞无效变体。我们的研究拓宽了双原发癌的变异谱，并为MSH2蛋白异常丢失和双原发癌的分子基础提供了见解。
