Early-onset diffuse gastric cancer associated with a de novo large genomic deletion of CDH1 gene
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A 41-year-old man with no familial history of gastric cancer was diagnosed as with intramucosal early gastric cancer. Two months after the first endoscopic submucosal dissection for signet-ring cell carcinoma (SRCC), the appearance of previously unrecognized multiple erosions of SRCC was noticed. Pathological examination after a total gastrectomy and Roux-en-Y reconstruction with D2 lymph node dissection were performed. Postoperative pathological examination revealed 90 and more lesions, which tempted the attending pathologist to refer to genetic tests for the predisposition though the patient had no familial history of gastric cancer. There were no mutations in all the exons of CDH1 with conventional DNA sequencing, but multiplex ligation-dependent probe amplification, and reverse transcription-polymerase chain reaction analyses disclosed a large genomic deletion (c.1566-?_1711+?del), leading to the mRNA with loss of the exon 11. Among family members, his son was found to be a carrier of this change, while his parents were negative for the familial CDH1 mutation, implying that this change is a de novo event in the proband. The present report is the first description of a de novo large genomic deletion of CDH1 gene associated with early-onset diffuse gastric cancer. When the clinician finds a relatively-young patient who has multiple SRCCs, CDH1 germline mutation should be considered, even for patients with no familial history.
KeywordsEndoscopic submucosal dissection Signet-ring cell carcinoma Stomach neoplasms CDH1 Mutation
Endoscopic submucosal dissection (ESD) is the preferred treatment method for locally dissecting early gastric cancer (EGC) with a negligible risk of lymph node metastasis . Currently nearly 100 % curability has been achieved for EGC with radical surgery, thus ESD is also expected to be performed at a comparable success rate. Metachronous recurrence of EGC after ESD is an important problem, but recurrence can be detected with adequate follow-up endogastroduodenoscopy (EGD), and most patients can receive early endoscopic treatment again . In Japan, the previous consensus has recommended curative ESD that are indicated only for small intramucosal differentiated-type EGC . Recently, the criteria have been expanded to other pathological types such as the undifferentiated-type under regulated conditions [3, 4, 5].
In Japan, gastric cancer is a major cause of cancer death, and Helicobacter pylori infection is considered to be a major cause of gastric cancer . Although epidemiological studies have shown that there are patients who have a significant familial history of gastric cancer, the pathogenesis of familial gastric cancer (FGC) has not been clearly explained. CDH1 germline mutations are associated with the development of autosomal cancer syndrome, namely hereditary diffuse gastric cancer (HDGC); about 25–30 % of families fulfilling the clinical criteria for HDGC established by the International Gastric Cancer Linkage Consortium (IGCLC) have constitutional alterations of the CDH1 gene . The CDH1 gene maps to chromosome 16q22.1 and consists of 16 exons that encode E-cadherin, which is a major component of adherens junctions. Carrying the abnormal CDH1 gene confers more than an 80 % lifetime risk of developing gastric cancer.
In 2012, the first conclusive case of a de novo CDH1 germline mutation (c.1792 C>T (R598X)) in a woman whose daughter was diagnosed with early-onset diffuse gastric cancer was reported . On the other hand, CDH1 germline mutations can also be identified in sporadic early-onset gastric cancer in less than 4 % of patients who are 35 years of age at the time of diagnosis, presenting as de novo mutations . Although the incidence of gastric cancer is relatively high in Japan, the detection rate of CDH1 germline mutations in Japanese patients with FGC is low compared to that in European patients .
We report the first case of early-onset diffuse gastric cancer associated with a de novo large genomic deletion of CDH1 gene, and the pathological feature including gross appearance of the surgical specimen of the stomach was pathognomonic.
After informed consent was obtained, DNA was extracted from the peripheral blood of the patient. First, a polymerase chain reaction (PCR)-direct sequencing analysis was performed for all the exons of CDH1, but no mutations were identified. Next, a multiplex ligation dependent probe amplification (MLPA) analysis was performed as previously described  (Fig. 4a). This revealed that the exon 11 of the CDH1 transcript was heterozygously deleted in this case; thus, a heterozygous c.1566-?_1711+?del germline mutation existed in the proband. For validation, CDH1 copy numbers in exons 11 were measured using TaqMan copy number assays according to the manufacturer’s instructions, and the copy number was 1 (the normal copy number is 2) (Fig. 4b).
E-cadherin is a calcium-dependent cell membrane protein involved in cell–cell adhesion and confers cell polarity . CDH1 mutations are associated with a risk of early-onset diffuse gastric cancer, in addition to increased risk of lobular breast cancer and signet-ring colon cancer . There was a report of six patients from one large kindred who underwent total gastrectomy for CDH1 mutation without any evidence of gastric cancer from detailed preoperative imaging studies, including high magnification endoscopy with methylene blue chromoendoscopy and multiple random biopsies. Each patient was found to have multiple sites of invasive diffuse SRCC without lymph node metastases . The guideline recommends advising CDH1 mutation positive patients with normal gastric biopsies to undergo prophylactic gastrectomy once the genetic testing results are known and once individuals are older than 20 years. Rare cases of clinically significant diffuse gastric cancer have been reported in affected families before the age of 18, but the overall risk of diffuse gastric cancer before the age of 20 is low . In the present case, the proband’s children should receive surveillance EGD in the future.
To date, over 100 kindreds with CDH1 germline mutations have been identified, and few cases of a concluded de novo CDH1 germline mutation have been reported . However, we think there are many unidentified patients who were not tested or in whom mutations could not be identified with conventional DNA sequencing. Importantly, 4 % of these mutation positive families exhibited large germline deletions of CDH1 that were not detectable with conventional DNA sequencing . Analyses of large genomic deletions with MLPA are recommended in cases where simple DNA sequencing is unrevealing [16, 17]. We propose that screening for germline large rearrangements of CDH1 should be included in CDH1 genetic testing for FGC in young patients with diffuse gastric cancer .
The present report is the first description of a de novo large genomic deletion of the CDH1 gene associated with the production of a truncated CDH1 protein. The c.1566-?_1711+?del germline mutation observed in this case has not been reported previously either as a somatic or a germline mutation, so we think this is novel and further characterization of its RNA would be interesting. Importantly, it was verified that this mutation passes the gene on to the proband’s offspring without change.
The ESD technique has rapidly permeated worldwide for treating EGC, but obviously it is not suitable for multiple occurrences such as in CDH1 mutation positive patients. As this instructive case shows, unusual morphologic feature may suggest prepared endoscopists should suspect genetic predisposition. In such a case, genetic counseling should also be provided. A prudent follow-up is necessary not only for the proband but also for the proband’s family. When a clinician finds the relatively-young patient who has multiple SRCCs, unusual conditions such as CDH1 germline mutation should be considered, even if patients have no familial histories of gastric cancer.
This work was supported by grants from the Ministry of Health, Labour and Welfare (10103838), Ministry of Education, Culture, Sports, Science and Technology (S-001), National Cancer Center Research and Development Fund, Princess Takamatsu Cancer Research Fund, and the Smoking Research Foundation.
Conflict of interest
- 17.Kim S, Chung JW, Jeong TD, Park YS, Lee JH, Ahn JY, et al. Searching for E-cadherin gene mutations in early onset diffuse gastric cancer and hereditary diffuse gastric cancer in Korean patients. Fam Cancer 2012 (Epub ahead of print).Google Scholar
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