Hereditary Diffuse Gastric Cancer in a Japanese Family with CDH1 Mutation: Three Individuals Undergoing Total Gastrectomy Following Presymptomatic Genomic Diagnosis

doi:10.21203/rs.3.rs-2232044/v1

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Case Report

Hereditary Diffuse Gastric Cancer in a Japanese Family with CDH1 Mutation: Three Individuals Undergoing Total Gastrectomy Following Presymptomatic Genomic Diagnosis

https://doi.org/10.21203/rs.3.rs-2232044/v1

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Background;

Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan.

Method;

Here, we describe four cases of HDGC in a single Japanese family.

Results;

The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in three relatives, which revealed abnormal small pale mucosal patches, small ulcerative lesion, and no abnormal findings, respectively. Random and targeted biopsies were compatible with the pathological diagnosis of HDGC. They underwent total gastrectomy and Roux-en-Y reconstruction with D2 lymph node dissection.

Conclusion;

In the management of HDGC, multidisciplinary and family-oriented approaches are critical, including genetic analysis of CDH1 variants in the proband, presymptomatic diagnosis of at-risk relatives through careful genetic counseling, and random biopsy-based surgery or prophylactic total gastrectomy.

Hereditary diffuse gastric cancer

hereditary cancer

signet cell adenocarcinoma

endoscopic diagnosis

random biopsy

Hereditary diffuse gastric cancer (HDGC) is a heritable form of gastric cancer [1–5]. Approximately 40% of families with HDGC were reported to have germline heterozygous pathogenic variants in CDH1, which encodes E-cadherin [6]. E-cadherin is a calcium-dependent cell membrane protein involved in cell–cell adhesion that is a known tumor suppressor. The cumulative risk of diffuse gastric cancer in patients with CDH1-related HDGC is approximately 70% for men and 56% for women [2]. HDGC accounts for 1% of all gastric cancers [3], and the majority of cases of CDH1-related HDGC reported to date have been in Western countries [7]. Despite the high incidences of gastric cancers in East Asian countries compared with Western countries, HDGC harboring CDH 1 variants has rarely been reported. Although several Japanese HDGC families with CDH 1 variant have been reported to date [8–13], awareness of this clinical entity remains low.

We encountered a patient with advanced gastric cancer with a family history of gastric cancer in whom a previously reported pathogenic variant in CDH1 was identified, followed by presymptomatic molecular diagnosis and random biopsy-based aggressive surgical intervention in three at-risk relatives. Here, we report the clinical manifestations in these cases with a review of the relevant literature.

The pedigree of this family is shown in Fig. 1. The proband (III-5) was a 51-year-old man admitted to our hospital for further therapy due to postoperative gastric cancer recurrence. He underwent total gastrectomy with D2 lymphadenectomy 1 year prior to this admission. Pathological examination revealed adenocarcinoma, with pathological stage T4aN3M0 according to the Union for International Cancer Control (UICC) TNM Classification of Malignant Tumours, 8th Edition. He was treated with tegafur/gimeracil/oteracil adjuvant chemotherapy. However, he developed bowel obstruction due to peritoneal dissemination 10 months after the initial surgery. He received chemotherapy for 8 months, but died due to uncontrollable progression of the disease. His maternal grandfather (I-1) and aunt (II-4), mother (II-2), and elder sister (III-4) had all developed gastric cancer resulting in early death. A family history of gastric cancer was suggested to constitute HDGC, according to the International Gastric Cancer Linkage Consortium clinical criteria for HDGC [3]. After obtaining appropriate informed consent from this patient, genetic investigation was performed using genomic DNA extracted from his peripheral blood leukocytes. A previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12) was detected in the proband. After careful genetic counseling of at-risk relatives (multisession-based decision making, anticipatory guidance, and psychosocial considerations), three sisters (III-2, 3, 6) and two nieces (IV-3, 5) of the patient underwent presymptomatic molecular investigation. Three of these family members (III-2, 6, and IV-3) were found to have the variant. These procedures and this study were approved by the Shinshu University School of Medicine Biological and Medical Research Ethics Committee (approval No. 648) and Ethics Committee of Hamamatsu University School of Medicine (approval No. 20 − 011), respectively. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Written informed consent to be included in the study participate and publishing their images was obtained from all subjects.

Case III-6

Case III-6 had no prior history relevant to cancer. She underwent molecular diagnosis at age 49 years, and there were no abnormal findings on physical or blood examination, including tumor markers CEA (2.0 ng/mL; normal range, 0.0–3.4) and CA19-9 (0.8 U/mL; normal range, 0.0–37.0). Esophagogastroduodenoscopy showed a type 0-IIa + IIc lesion at the gastric fundus with ulcers in the center of the lesion (Fig. 2A). Histology of biopsy specimens taken from the lesion indicated signet-ring cell carcinoma and poorly differentiated adenocarcinoma. The depth of cancer invasion was considered to be below the submucosal layer. Neither computed tomography (CT) nor ¹⁸F-fluorodeoxy glucose positron emission tomography (FDG-PET) revealed any distant metastasis or lymph node involvement. Therefore, preoperative stage was considered to be T1b (SM), N0, M0, with clinical stage IA. She underwent laparoscopic total gastrectomy. Laparoscopic findings revealed no ascites or peritoneal dissemination. The extent of lymph node dissection was D2. Macroscopically, the size of the tumor was 7.5 × 5.2 cm; the type 3 tumor was found in the upper back wall of the stomach (Fig. 2B); microscopically, the tumor was diagnosed as poorly differentiated adenocarcinoma (por2) and signet ring cell carcinoma, and the depth of tumor was T4a (serosal invasion); the number of dissected lymph nodes was 32, and one (# 2 lymph node) was found to have metastasis. According to the UICC TNM classification, the tumor was diagnosed as pT4N1M0 stage IIIA. In addition, a total of 20 lesions of intramucosal signet-ring cell carcinoma measuring about 2 mm were found in the stomach (Fig. 3A and B). Capecitabine plus oxaliplatin was given as adjuvant chemotherapy for 6 months, resulting in recurrence-free survival for 46 months.

Case III-2

Case III-2 had no prior history relevant to cancer. She underwent molecular diagnosis at age 62 years, and physical examination showed no specific findings except operational scars in the abdomen associated with past surgery for appendicitis at age 14 years. Blood examination revealed no abnormal finding, including tumor markers CEA (2.2 ng/mL) and CA19-9 (1.9 U/mL). Upper gastrointestinal endoscopy showed a small type 0-IIb lesion in the gastric pyloric zone (Fig. 4A). Histology of the biopsy specimens taken from the lesion indicated signet-ring cell carcinoma. The depth of cancer invasion was considered to be to the mucosal layer. Neither CT nor FDG-PET revealed any distant metastasis or lymph node involvement. Therefore, preoperative stage was considered to be T1a(M), N0, M0, and clinical stage was IA. She underwent laparoscopic total gastrectomy. There was no ascites or peritoneal dissemination. A total of seven tumors with diameter < 1 mm were observed and pathological diagnosis of all the tumors was signet ring cell carcinoma (Fig. 4B). The depth of invasion was T1a(M) in all lesions. The number of dissected lymph nodes was 58 and no lymph node metastasis was found. According to the UICC TNM classification, a diagnosis of pT1aN0M0 stage IA was made. She had no recurrence at 45 months after the operation.

Case IV-3

Case IV-3 had no prior history relevant to cancer. She underwent molecular diagnosis at age 35 years, and physical and blood examination revealed no abnormal findings, including tumor markers CEA (2.7 ng/mL) and CA19-9 (1.4 U/mL). Esophagogastroduodenoscopy showed only superficial gastritis. Random biopsies were taken from 25 locations. Atypical cells were detected in one biopsy specimen, which was diagnosed as signet ring cell carcinoma. The depth of cancer invasion was considered to be the mucosal layer. Neither CT nor FDG-PET revealed any distant metastasis or lymph node involvement. Therefore, preoperative stage was considered to be T1a(M), N0, M0, and clinical stage was IA. She underwent laparoscopic total gastrectomy. There was no ascites and no peritoneal dissemination. A total of three tumors less than 1 mm in diameter were detected, and pathological diagnosis of all the tumors was signet ring cell carcinoma (Fig. 5). The depth of invasion was T1a (M) in all lesions. The number of dissected lymph nodes was 39, and no lymph node metastasis was found. According to the UICC TNM classification, the diagnosis was pT1aN0M0 stage IA. She had no recurrence at 31 months after the operation.

The medical history of the family described here was compatible with HDGC (1–3), and molecular investigation revealed a frameshift variant in CDH1 that would result in truncation of the protein (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12), as reported previously in a series by Benusiglio et al. (14) and also registered as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/). Although several Japanese families with CDH 1-related HDGC have been reported [8–13], to our knowledge, this is the largest number of family members with HDGC reported to date, including the proband who died due to gastric cancer.

Serial screening gastroscopy is important for subjects with evidence of CDH1 mutation (15,16). Several studies showed that careful examination with targeted and random biopsies combined with detailed histopathology can identify early lesions and inform decision making for gastrectomy (15,16). Histopathological diagnoses of HDGC were made in three at-risk family members, which enabled prompt decision for prophylactic surgery. Consequently, relatively good survival was obtained in all three cases without recurrence. However, in case III-6, the preoperative diagnosis was T1b(sm), N0, M0 with clinical stage IA indicating early cancer. Operative observations revealed an unexpectedly advanced tumor, accompanied by lymph node metastasis 7.5 cm × 5.2 cm in diameter with serosal involvement (T4a). Therefore, adjuvant chemotherapy (capecitabine plus oxaliplatin) was introduced in this case. Considering the advanced lesions in postoperative specimens in case III-6, surveillance alone would not be sufficient, and prophylactic total gastrectomy could be a rational intervention for better prognosis in HDGC. Therefore, we intend to make presymptomatic diagnosis and perform early surveillance and intervention in patients with suspicion of familial gastric cancer.

Based on the international guidelines (4), prophylactic total gastrectomy is recommended as standard of care in carriers of a pathogenic CDH1 mutation. This should be performed in early adulthood up to around 30 years of age (4). However, the optimal timing of surgical intervention remains to be determined. In addition, in Japan, prophylactic gastrectomy without a diagnosis of cancer is problematic with regard to not only insurance, but is also an ethical issue. Prophylactic total gastrectomy in young patients requires preoperative understanding of the patient based on adequate informed consent and counseling, as well as appropriate postoperative follow-up. Muir et al. (17) performed a prospective cohort study to examine the decision-making process of subjects undergoing prophylactic total gastrectomy, as well as physical and psychosocial outcomes, and described persistent mild physical symptoms affecting long-term quality of life (17). Therefore, we emphasized that a multidisciplinary team involving surgeons, dieticians, genetic counselors, and specialist nurses would be necessary. Furthermore, as HDGC families are extremely rare in Japan, in view of public opinion against prophylactic gastrectomy, it may be necessary for academic societies to take the initiative in establishing treatment guidelines for prophylactic surgery.

In the present family, the age of death due to gastric cancer ranged from 35 to 84 years old. In general, the onset of the disease occurs at a young age (8–13). In other Japanese families with CDH1 mutation, most cases reported were in their 20s or 30s (5–13). The age distribution in the present family may have been related to other factors contributing to the development of gastric cancer. Further clinical experience and genetic background are required in Japanese subjects positive for CDH1 mutation.

In summary, although HDGC has been regarded as rare in East Asia, we emphasize that CDH1 germline mutation testing should be considered in patients with a familial history of gastric cancer, and careful examination and random biopsies using esophagogastroduodenoscopy are necessary in patients with suspicion of HDGC.

Funding

This research was supported in part by Japan Agency for Medical Research and Development (AMED) under Grand Number JP22ck0106554.

Conflict of Interest Statement

Tomoki Kosho is a member of an endowed chair named “Division of Clinical Sequencing, Shinshu University School of Medicine” sponsored by BML, Inc. and Life Technologies Japan Ltd. of Thermo Fisher Scientific Inc. The other authors have no relevant financial support

Data availability

All data analyzed during this study are included in this published article.

Authors Contributions

All authors contributed to the study conception and design. Medical treatment was performed by Daisuke Gomi and Tomonobu Koizumi. Endoscopic surveillance was performed by Tomoaki Suga. Surgical treatment was performed by Futoshi Muranaka, Shigeo Tokumaru, Masato Kitazawa, Yusuke Miyagawa and Yuji Soejima. Pathological examination was performed by Takeshi Uehara, Mai Iwaya, Shota Kobayashi, and Midori Sato. Genetic analysis was performed by Haruhiko Sugimura, Hidetaka,Yamada and Tomoki Kosho. Genetic counseling was performed by Emiko Kise and Tomoki Kosyo. The first draft of the manuscript was written by Futoshi Muranaka, Tomoki Kosho and Tomonobu Koizumi. Emiko Kise and Tomoki Kosho prepared Figure 1. Takeshi Uehara, Mai Iwaya, Shota Kobayashi, and Midori Sato prepared Figure 2-5. All authors read and approved the final manuscript.

Ethics approval and consent to participate

This study was approved by the Shinshu University School of Medicine Biological and Medical Research Ethics Committee (approval No. 648) and Ethics Committee of Hamamatsu University School of Medicine (approval No. 20-011), respectively. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Written informed consent to be included in the study participate and publishing their images was obtained from all subjects.

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No competing interests reported.

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You are reading this latest preprint version

Hereditary Diffuse Gastric Cancer in a Japanese Family with CDH1 Mutation: Three Individuals Undergoing Total Gastrectomy Following Presymptomatic Genomic Diagnosis

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Abstract

Background;

Method;

Results;

Conclusion;

Figures

Introduction

Case Presentation

Discussion

Declarations

References

Additional Declarations

Status:

Version 1