Alternative titles; symbols
ORPHA: 314022;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q22.2 | Gastric adenocarcinoma and proximal polyposis of the stomach | 619182 | Autosomal dominant | 3 | APC | 611731 |
A number sign (#) is used with this entry because of evidence that gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is caused by heterozygous mutation in the APC gene (611731) promoter 1B on chromosome 5q22.
Heterozygous mutation in the APC gene also causes familial adenomatous polyposis (see FAP1, 175100).
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is characterized by autosomal dominant transmission of fundic gland polyposis (FGP) with occasional hyperplastic and adenomatous polyps, sparing of the gastric antrum, and the development of intestinal-type gastric adenocarcinoma. Colorectal polyposis is not observed, and family history does not include colorectal cancer (Worthley et al., 2012).
Fundic gland polyposis (FGP) is marked by the presence of varying numbers of small, sessile polyps restricted to the body and fundus of the stomach. Histologically, it is characterized by proliferation of the fundic glands and cystically dilated glandular ducts. This finding was initially described by Japanese investigators as gastric lesions of familial polyposis coli and Gardner syndrome (Utsunomiya et al., 1974; Watanabe et al., 1978). FGP was also described in patients with no family history and no polyposis of the colon. Lee and Burt (1986) found no histologic differences between FGP with or without polyposis of the colon. Tsuchikame et al. (1993) described FGP without polyposis coli in a 16-year-old female and subsequently in her 42-year-old mother and 48-year-old father. During a follow-up period of 11 years, no polyps were detected in the antrum, pylorus, duodenum, or colon in the 3 patients, and no extra-alimentary manifestations of Gardner syndrome were found.
Dos Santos and de Magalhaes (1980) described a family in which 10 members of 3 generations had multiple polyposis, with adenocarcinomatous propensities, limited to the stomach. Seruca et al. (1991) restudied the family reported by dos Santos and de Magalhaes (1980) and added an observation of male-to-male transmission, suggesting autosomal dominant inheritance. The histology of the gastric polyps present in the affected members revealed signet ring cell type carcinoma. Severe psoriasis was present in some members of the family as a probable coincidental disorder.
Worthley et al. (2012) described 3 unrelated families segregating autosomal dominant proximal gastric polyposis, including a large 4-generation family from Australia and 2 smaller 3-generation families from the United States and Canada. In the Australian family, there were 20 affected family members, and fundic gland polyposis was detected as early as 10 years of age. There were 2 family members with typical proximal polyposis of the stomach who died from intestinal-type gastric adenocarcinoma at ages 33 and 48 years; both developed liver metastases. Although all individuals represented in the 3 pedigrees were masked for sex, the authors stated that there was a 1:2.3 male:female ratio in the Australian family, with 4 instances of male-to-male transmission. In addition, 3 obligate carriers had normal upper gastrointestinal endoscopies at 68, 72, and 77 years of age, indicating incomplete penetrance. One affected individual underwent capsule endoscopy that excluded polyps of the small intestine. Colonoscopy results were available from 13 affected family members, none of whom had colorectal polyposis; the most advanced colorectal pathology involved 8 simple tubular adenomas removed over 4 colonoscopies, and there was no family history of colorectal cancer. In the other 2 families, 3 of 7 and 2 of 4 affected individuals, respectively, developed gastric cancer, the youngest at age 34 years. Colonoscopy was reported to be unremarkable in 3 affected family members from the 2 families. In the Canadian family, there were 4 family members with other cancers, including 1 case each of leukemia, brain, prostate, and lung cancer. The authors designated the phenotype 'gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS).'
Repak et al. (2016) reported a Czech family in which a father, 3 daughters, and the paternal grandmother had GAPPS. The father presented with melena at age 54 years, and was found to have fundic polyposis; histopathology was typical and showed no dysplasia. No polyps were present in the gastric antrum or duodenum; colorectal findings were normal apart from 3 adenomas of the colon that were removed. Within 2 years, he developed liver metastases and ascites, and died following palliative chemotherapy. Liver biopsy had shown moderately differentiated adenocarcinoma of the intestinal type, and autopsy revealed the same histopathology in the gastric body. The proband's mother also had proximal gastric polyposis, and had died of gastric cancer involving the fundus at age 49 years. The proband had 3 daughters with fundic gland polyposis and no colon polyps. Repeat gastroscopies showed rapid progression, and 1 daughter died at age 26 with liver metastases, ascites, and peritoneal, mesenteric, and omental infiltration. Autopsy showed poorly differentiated gastric adenocarcinoma of the intestinal type. The other 2 daughters underwent prophylactic total gastrectomies, and histology revealed stage 1A gastric adenocarcinoma in both cases.
Beer et al. (2017) reported an Austrian woman who presented at age 28 years with upper abdominal pain and was found to have numerous FGPs in the fundus and body of the stomach, whereas her small and large intestines were free of polyps. Follow-up gastroscopies revealed more FGPs, and histologic analysis showed low-grade intraepithelial neoplasia (IEN) in some of the polyps. At age 38, post-gastroscopy analysis of the polyps revealed high-grade IEN, and she underwent prophylactic gastrectomy; macroscopic examination of the gastrectomy specimen showed hundreds of 3-mm polyps covering the fundus and corpus. Her father had died of gastric cancer at age 57 years.
Foretova et al. (2019) studied 8 Czech families with GAPPS and a mutation in the APC promoter 1B. Of the 24 carriers of the mutation, 20 had massive gastric polyposis, with more than 100 fundic glandular polyps diagnosed between the ages of 25 years and 65 years. Five had already died of adenocarcinoma of the stomach at ages 29, 40, 59, 60, and 64 years, and 1 who underwent gastrectomy at age 29 was found to have tubulopapillary adenocarcinoma with 2 positive lymph nodes. One female carrier had incipient polyposis at age 58 years; 2 female carriers did not have polyposis of the stomach at ages 31 and 65; and a 92-year-old asymptomatic male carrier did not undergo gastroscopy due to his advanced age. Of 6 reported colonoscopies, 2 were negative for polyps and the others showed fewer than 4 polyps.
Kanemitsu et al. (2021) reported 2 unrelated Japanese families with GAPPS. In family 1, 2 sisters with FGPs and no duodenal or colonic polyps underwent laparoscopic gastrectomy with lymph node dissection after endoscopic biopsies showed gastric cancer. They were alive and free of disease at 5 years after surgery. Their mother had died at age 63 years of gastric cancer with fundic polyposis, and the published family pedigree showed that the mother's sister also had gastric cancer. In family 2, a father and daughter had FGPs without duodenal or colonic polyps. Biopsies showed gastric cancer in the 57-year-old father and severe dysplasia with adenocarcinoma in situ in the 24-year-old daughter, and both underwent laparoscopic gastrectomy. The published family pedigree indicated 4 additional family members with gastric polyposis, including the paternal grandmother.
Worthley et al. (2012) suggested the following diagnostic criteria for GAPPS: gastric polyps restricted to the body and fundus with no evidence of colorectal or duodenal polyposis; more than 100 polyps carpeting the proximal stomach in the index case, or more than 30 polyps in a first-degree relative of another case; predominantly fundic gland polyps, with some having regions of dysplasia, or a family member with either dysplastic FGPs or gastric adenocarcinoma; and an autosomal dominant pattern of inheritance. The authors noted that other heritable gastric polyposis syndromes and FGPs associated with use of proton-pump inhibitors (PPIs) should be excluded, and suggested that in the case of patients on PPIs, repeat endoscopy off therapy should be performed.
The transmission pattern of GAPPS in the 3 families reported by Worthley et al. (2012) was consistent with autosomal dominant inheritance.
Li et al. (2016) performed linkage analysis in a large 5-generation Australian family with GAPPS, originally reported by Worthley et al. (2012), and found linkage to a 46-Mb region on chromosome 5 including the APC gene (611731), with a maximum lod score of 4.51.
In a large 5-generation Australian family segregating autosomal dominant adenomatous polyposis of the proximal stomach mapping to chromosome 5, originally described by Worthley et al. (2012), in which whole-exome and whole-genome sequencing failed to identify a causative mutation, Li et al. (2016) sequenced the 2 APC promoters (see 611731) and identified a point mutation and a 1-bp deletion (c.-195A-C and c.-125delA; 611731.0053), both located on the same allele of the APC promoter 1B, that completely cosegregated with disease in the family. Analysis of 5 additional families, including 1 US and 1 Canadian family studied by Worthley et al. (2012), revealed a heterozygous c.-191T-C variant (611731.0054) segregating with disease in 4 of the families, and a heterozygous c.192A-G change (611731.0055) in both affected members of the Canadian family. The changes were not found in public variant databases. Analysis of fundic gland polyps from the Australian family confirmed the germline promoter 1B mutations and also revealed 4 somatic truncating APC mutations, present at estimated mutant allele frequencies of 31%, 12%, 9% and 8%. Li et al. (2016) proposed that APC haploinsufficiency is responsible for the fundic gland polyposis, whereas the second APC hit might be the driver of dysplasia.
In a father and 3 daughters from a 3-generation Czech family segregating autosomal dominant GAPPS, who were negative for mutation in 17 other hereditary gastrointestinal cancer-associated genes, Repak et al. (2016) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B.
In a 38-year-old Austrian woman with GAPPS, Beer et al. (2017) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B.
In 24 individuals from 8 Czech families with GAPPS, Foretova et al. (2019) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B. Of the 24 mutation carriers, 20 had massive gastric polyposis; in addition, 1 female carrier had incipient polyposis at age 58 years; 2 female carriers did not have polyposis of the stomach at ages 31 and 65; and a 92-year-old asymptomatic male carrier did not undergo gastroscopy due to his advanced age.
In affected members of 2 multiplex Japanese families with GAPPS, Kanemitsu et al. (2021) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B.
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Kanemitsu, K., Iwatsuki, M., Yamashita, K., Komohara, Y., Morinaga, T., Iwagami, S., Eto, K., Nagai, Y., Kurashige, J., Baba, Y., Yoshida, N., Baba, H. Two Asian families with gastric adenocarcinoma and proximal polyposis of the stomach successfully treated via laparoscopic total gastrectomy. Clin. J. Gastroent. 14: 92-97, 2021. [PubMed: 33242120] [Full Text: https://doi.org/10.1007/s12328-020-01290-6]
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Repak, R., Kohoutova, D., Podhola, M., Rejchrt, S., Minarik, M., Benesova, L., Lesko, M., Bures, J. The first European family with gastric adenocarcinoma and proximal polyposis of the stomach: case report and review of the literature. Gastrointest. Endosc. 84: 718-725, 2016. [PubMed: 27343414] [Full Text: https://doi.org/10.1016/j.gie.2016.06.023]
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Worthley, D. L., Phillips, K. D., Wayte, N., Schrader, K. A., Healey, S., Kaurah, P., Shulkes, A., Grimpen, F., Clouston, A., Moore, D., Cullen, D., Ormonde, D., Mounkley, D., Wen, X., Lindor, N., Carneiro, F., Huntsman, D. G., Chenevix-Trench, G., Suthers, G. K. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome. Gut 61: 774-779, 2012. Note: Erratum: Gut 61: 1305 only, 2012. [PubMed: 21813476] [Full Text: https://doi.org/10.1136/gutjnl-2011-300348]