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Gastric Cancer

October 12, 2017

Disease synonyms

Hereditary diffuse gastric cancer, HDGC, Familial diffuse gastric cancer


Inheritance pattern

Autosomal dominant, somatic


Clinical features

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant susceptibility for diffuse gastric cancer, a poorly differentiated adenocarcinoma localized in the stomach wall. Gastric cancer is one of the most common cancers in the world, with the highest incidence rates in Japan (80 cases per 100,000) and eastern Asia 1. Other areas of the world with a high incidence of stomach cancer include Eastern Europe and parts of Latin America. Incidence rates are generally lower in Western Europe and the United States (10-40:100,000) 1. The incidence rate of diffuse-type gastric cancer in the US was reported to be ~62% 2.

According to the International Gastric Cancer Linkage Consortium (IGCLC) consensus guidelines 3, clinical criteria for the genetic screening of families with suspected hereditary gastric cancer include one of the following:

  • Two gastric cancer (GC) cases in a family, in which one individual developed confirmed diffuse gastric cancer (DGC) under age 50 years
  • Three confirmed individuals with DGC in first- or second-degree relatives, independent of age
  • A simplex case (i.e., a single occurrence in a family) of DGC occurring before age 40 years
  • Personal or family history of DGC and lobular breast cancer, one diagnosed before age 50 years.

The majority of the gastric cancers occur before age 40, but the age of onset is variable both between and within families 1. Presenting symptoms are nonspecific in the early stages of the disease. Symptoms in the late stage may include abdominal pain, nausea, vomiting, dysphagia, postprandial fullness, loss of appetite, and weight loss. Late in the course of stomach cancer, a palpable mass may be present. Tumor spread or metastasis may lead to an enlarged liver, jaundice, ascites, skin nodules, and fractures. Other cancers reported in family members include most commonly lobular breast cancer and colorectal cancer.

Gastric cancer is seen in several other cancer predisposition syndromes, including Lynch syndrome, Li-Fraumeni syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome and Cowden syndrome.

Lynch syndrome, which is associated with germline pathogenic variants in mismatch repair genes, predisposes heterozygotes to colorectal and other cancers. Gastric cancer is the third most common cancer in these individuals. IGC is the predominant subtype in Lynch syndrome 4.

Microsatellite instability (MSI) was observed in approximately 15% of gastric cancers from individuals in Florence, Italy, an area with high gastric cancer risk 5. Gastric cancers with high MSI tend to occur in the antrum of the stomach, be of the intestinal type, and offer better survival rates.

Familial adenomatous polyposis (FAP) is caused by germline pathogenic variants in APC. Gastric cancer has been seen in 0.6% of persons with FAP 6.

Cancers associated with Li-Fraumeni syndrome are caused by pathogenic variants in either TP53 or CHEK2. Both DGC and IGC are observed 7.

An increased risk of gastric cancer has been associated with pathogenic variants in BRCA1 and BRCA2 8, 9. Gastric cancer occurs in 5.7% of families with the BRCA2 6174delT pathogenic variant 10. In a subset (7%) of individuals with gastric cancer, a BRCA2 pathogenic variant may be the underlying genetic cause 11.

Hereditary diffuse gastric cancer is caused by a heterozygous germline variant in the E-cadherin gene (CDH1) on chromosome 16q22. A somatic variant in the CDH1 gene has also been found in patients with sporadic diffuse gastric cancer and lobular breast cancer. In addition to CDH1, several other genes have been associated with gastric cancer: BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, PMS1, PMS2, SMAD4 (table).


Gene OMIM (Gene) Associated diseases (OMIM) Inheritance
APC 611731 colorectal cancer; Hepatocellular Carcinoma; Desmoid disease, hereditary; familial adenomatous polyposis; Gastric Cancer AD
ATM 607585 familial breast-ovarian cancer type 2; ataxia-telangiectasia AD, AR
AXIN2 604025 colorectal cancer; oligodontia-colorectal cancer syndrome AD
BLM 604610 Bloom syndrome AR
BMPR1A 601299 Juvenile polyposis syndrome, infantile form AD
BRCA1 113705 familial breast-ovarian cancer type 1; pancreatic cancer type 4; Fanconi anemia, complementation group S AD, AR
BRCA2 600185 familial breast-ovarian cancer type 2; Medulloblastoma; Prostate Cancer; Wilms tumor, type 1; Fanconi anemia complementation group D1; pancreatic cancer type 2 AD, AR
CDH1 192090 familial breast-ovarian cancer type 2; blepharocheilodontic syndrome 1; Gastric Cancer, Hereditary Diffuse; Ovarian Cancer; Prostate Cancer; endometrial cancer AD
CDKN2A 600160 Malignant melanoma 2; Pancreatic cancer/melanoma syndrome AD
CHEK2 604373 familial breast-ovarian cancer type 2; Prostate Cancer; Osteogenic Sarcoma; Li-Fraumeni syndrome 2 AD
EPCAM 185535 Diarrhea 5, with tufting enteropathy, congenital; Colorectal cancer, hereditary nonpolyposis, type 8 AR
FLCN 607273 colorectal cancer; Birt-Hogg-Dube syndrome; Renal carcinoma, chromophobe, somatic; primary spontaneous pneumothorax AD
GALNT12 610290 Colorectal cancer, susceptibility to, 1
MLH1 120436 Muir-Torre syndrome; mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-2 AD, AR
MLH3 604395 colorectal cancer; endometrial cancer; Colorectal cancer, hereditary nonpolyposis, type 7 AD
MSH2 609309 Lynch syndrome; Muir-Torre syndrome; mismatch repair cancer syndrome AD, AR
MSH3 600887 endometrial cancer; Familial adenomatous polyposis 4 AR
MSH6 600678 mismatch repair cancer syndrome; endometrial cancer; hereditary nonpolyposis colorectal cancer-5 AD, AR
MUTYH 604933 familial adenomatous polyposis type 2; Gastric Cancer AR
NBN 602667 Nijmegen breakage syndrome; Aplastic Anemia; Acute lymphoblastic leukemia AR
NTHL1 602656 Familial adenomatous polyposis 3 AR
PALB2 610355 familial breast-ovarian cancer type 2; Fanconi anemia of complementation group N; Pancreatic cancer, susceptibility to, 3 AD
PMS2 600259 mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-4 AR
POLD1 174761 Colorectal cancer, susceptibility to type 10; MANDIBULAR HYPOPLASIA, DEAFNESS, PROGEROID FEATURES, AND LIPODYSTROPHY SYNDROME AD
POLE 174762 Colorectal cancer, susceptibility to, 12; FILS syndrome AD, AR
PRSS1 276000 hereditary pancreatitis AD
PTEN 601728 Cowden syndrome 1; Cowden syndrome type 2; Bannayan-Riley-Ruvalcaba syndrome; Prostate Cancer; Macrocephaly/autism syndrome; Meningioma, familial, susceptibility to AD
RNF43 612482 AD
SMAD4 600993 Myhre syndrome; Juvenile polyposis syndrome, infantile form; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Pancreatic Cancer AD
STK11 602216 Peutz-Jeghers syndrome; Pancreatic Cancer; Spermatocytic seminoma, somatic AD
TGFBR2 190182 Esophageal cancer, somatic; Loeys-Dietz syndrome 2; Colorectal cancer, hereditary nonpolyposis, type 6 AD
TP53 191170 familial breast-ovarian cancer type 2; colorectal cancer; Hepatocellular Carcinoma; Glioma susceptibility 1; Li-Fraumeni syndrome 1; Osteogenic Sarcoma; Pancreatic Cancer AD
VHL 608537 Renal carcinoma, chromophobe, somatic; pheochromocytoma; von Hippel-Lindau disease; Erythrocytosis, familial, 2 AD, AR

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance
ABRAXAS1 611143
APC 611731 colorectal cancer; Hepatocellular Carcinoma; Desmoid disease, hereditary; familial adenomatous polyposis; Gastric Cancer AD
ATM 607585 familial breast-ovarian cancer type 2; ataxia-telangiectasia AD, AR
AXIN2 604025 colorectal cancer; oligodontia-colorectal cancer syndrome AD
BAP1 603089 Tumor predisposition syndrome AD
BARD1 601593 familial breast-ovarian cancer type 2 AD
BLM 604610 Bloom syndrome AR
BMPR1A 601299 Juvenile polyposis syndrome, infantile form AD
BRCA1 113705 familial breast-ovarian cancer type 1; pancreatic cancer type 4; Fanconi anemia, complementation group S AD, AR
BRCA2 600185 familial breast-ovarian cancer type 2; Medulloblastoma; Prostate Cancer; Wilms tumor, type 1; Fanconi anemia complementation group D1; pancreatic cancer type 2 AD, AR
BRIP1 605882 familial breast-ovarian cancer type 2; Fanconi anemia of complementation group J AD
CDH1 192090 familial breast-ovarian cancer type 2; blepharocheilodontic syndrome 1; Gastric Cancer, Hereditary Diffuse; Ovarian Cancer; Prostate Cancer; endometrial cancer AD
CDK4 123829 Melanoma, Cutaneous Malignant, Susceptibility To, 3 AD
CDKN2A 600160 Malignant melanoma 2; Pancreatic cancer/melanoma syndrome AD
CHEK2 604373 familial breast-ovarian cancer type 2; Prostate Cancer; Osteogenic Sarcoma; Li-Fraumeni syndrome 2 AD
DICER1 606241 Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors; Rhabdomyosarcoma, embryonal, 2; Pleuropulmonary blastoma AD
DIS3L2 614184 Perlman syndrome AR
EPCAM 185535 Diarrhea 5, with tufting enteropathy, congenital; Colorectal cancer, hereditary nonpolyposis, type 8 AR
FANCC 613899 Fanconi anemia of complementation group C AR
FH 136850 Leiomyomatosis and renal cell cancer; Fumarase deficiency AD, AR
FLCN 607273 colorectal cancer; Birt-Hogg-Dube syndrome; Renal carcinoma, chromophobe, somatic; primary spontaneous pneumothorax AD
GALNT12 610290 Colorectal cancer, susceptibility to, 1
HNF1B 189907 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 5; Renal carcinoma, chromophobe, somatic AD
HOXB13 604607 Hereditary prostate cancer type 9
KIT 164920 Mast cell disease; Piebaldism; Spermatocytic seminoma, somatic; acute myeloid leukemia; gastrointestinal stromal tumor AD
MC1R 155555 oculocutaneous albinism type 2; skin/hair/eye pigmentation 2; Melanoma, cutaneous malignant, susceptibility to, 5 AR
MEN1 613733 multiple endocrine neoplasia type 1 AD
MET 164860 Hepatocellular Carcinoma; Renal cell carcinoma, papillary; deafness type 97 AD, AR
MITF 156845 Albinism, Ocular, With Sensorineural Deafness; Tietz Syndrome; Waardenburg syndrome type 2A; Melanoma, Cutaneous Malignant, Susceptibility To, 8 AD, AR
MLH1 120436 Muir-Torre syndrome; mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-2 AD, AR
MLH3 604395 colorectal cancer; endometrial cancer; Colorectal cancer, hereditary nonpolyposis, type 7 AD
MRE11 600814 Ataxia-telangiectasia-like disorder type 1 AR
MSH2 609309 Lynch syndrome; Muir-Torre syndrome; mismatch repair cancer syndrome AD, AR
MSH3 600887 endometrial cancer; Familial adenomatous polyposis 4 AR
MSH6 600678 mismatch repair cancer syndrome; endometrial cancer; hereditary nonpolyposis colorectal cancer-5 AD, AR
MUTYH 604933 familial adenomatous polyposis type 2; Gastric Cancer AR
NBN 602667 Nijmegen breakage syndrome; Aplastic Anemia; Acute lymphoblastic leukemia AR
NF1 613113 neurofibromatosis type 1; Neurofibromatosis-Noonan syndrome; Leukemia, juvenile myelomonocytic AD
NTHL1 602656 Familial adenomatous polyposis 3 AR
PALB2 610355 familial breast-ovarian cancer type 2; Fanconi anemia of complementation group N; Pancreatic cancer, susceptibility to, 3 AD
PMS1 600258
PMS2 600259 mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-4 AR
POLD1 174761 Colorectal cancer, susceptibility to type 10; MANDIBULAR HYPOPLASIA, DEAFNESS, PROGEROID FEATURES, AND LIPODYSTROPHY SYNDROME AD
POLE 174762 Colorectal cancer, susceptibility to, 12; FILS syndrome AD, AR
POT1 606478 Melanoma, cutaneous malignant, susceptibility to, 10 AD
PRSS1 276000 hereditary pancreatitis AD
PTCH1 601309 Gorlin syndrome; Holoprosencephaly-7 AD
PTEN 601728 Cowden syndrome 1; Cowden syndrome type 2; Bannayan-Riley-Ruvalcaba syndrome; Prostate Cancer; Macrocephaly/autism syndrome; Meningioma, familial, susceptibility to AD
RAD50 604040 Nijmegen breakage syndrome-like disorder
RAD51C 602774 Fanconi anemia of complementation group O; Breast-ovarian cancer, familial, susceptibility to, 3 AR
RAD51D 602954 susceptibility to familial breast-ovarian cancer type 4
RECQL 600537
RET 164761 Hirschsprung disease; familial medullary thyroid carcinoma; multiple endocrine neoplasia 2B; pheochromocytoma; multiple endocrine neoplasia 2A; congenital central hypoventilation syndrome AD
RNF43 612482 AD
SDHA 600857 mitochondrial complex II deficiency; Leigh syndrome; dilated cardiomyopathy-1GG; paragangliomas type 5 AD, AR, M
SDHAF2 613019 paragangliomas type 2 AD
SDHB 185470 paragangliomas type 4; pheochromocytoma; gastrointestinal stromal tumor; paraganglioma and gastric stromal sarcoma AD
SDHC 602413 Paragangliomas 3; gastrointestinal stromal tumor; paraganglioma and gastric stromal sarcoma AD
SDHD 602690 paragangliomas 1; pheochromocytoma; mitochondrial complex II deficiency; paraganglioma and gastric stromal sarcoma AD, AR
SMAD4 600993 Myhre syndrome; Juvenile polyposis syndrome, infantile form; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Pancreatic Cancer AD
SMARCA4 603254 Rhabdoid tumor predisposition syndrome 2; mental retardation-16 AD
STK11 602216 Peutz-Jeghers syndrome; Pancreatic Cancer; Spermatocytic seminoma, somatic AD
TGFBR2 190182 Esophageal cancer, somatic; Loeys-Dietz syndrome 2; Colorectal cancer, hereditary nonpolyposis, type 6 AD
TP53 191170 familial breast-ovarian cancer type 2; colorectal cancer; Hepatocellular Carcinoma; Glioma susceptibility 1; Li-Fraumeni syndrome 1; Osteogenic Sarcoma; Pancreatic Cancer AD
TSC1 605284 tuberous sclerosis type 1 AD
TSC2 191092 tuberous sclerosis-2 AD
VHL 608537 Renal carcinoma, chromophobe, somatic; pheochromocytoma; von Hippel-Lindau disease; Erythrocytosis, familial, 2 AD, AR
WT1 607102 Frasier syndrome; Mesothelioma, somatic; Wilms tumor, type 1; Denys-Drash syndrome; Nephrotic syndrome, type 4; Meacham syndrome AD
XRCC2 600375 Fanconi anemia, complementation group U AR
XRCC3 600675 familial breast-ovarian cancer type 2 AD

With genetic testing, we are able today to providedetect detection of genetic gastric cancer susceptibility (for instance. HDGC) in order to prevent cancer development in affected patients and thereby reduce cancer mortality. Genetic testing for gastric cancer is also the most accurate means of determining the risk of hereditary gastric cancer.

Treatment of gastric cancer includes different approaches, such as surgery, chemotherapy, radiotherapy, and targeted therapy. Ideally, management of individuals who have a CDH1 cancer-predisposing variant is either intense surveillance for early detection and treatment of gastric cancer or prophylactic gastrectomy. Care by a multidisciplinary team comprising specialists with expertise in clinical genetics, gastric surgery, gastroenterology, pathology, and nutrition is recommended. For women, referral to a high-risk breast cancer clinic is recommended; prophylactic mastectomy may be considered.

CENTOGENE experts have designed the Gastric cancer panel which includes these genes: BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, PMS1, PMS2, SMAD4.


Differential diagnosis

The differential diagnosis of gastric cancer-related disorders – depending on the major symptoms in the initial case – includes the following diseases1:

  • Lynch syndrome, caused by pathogenic variant in one of the mismatch repair genes
  • Familial adenomatous polyposis (FAP), caused by germline pathogenic variants in APC gene
  • Li-Fraumeni syndrome, caused by pathogenic variants in either TP53 or CHEK2 genes
  • BRCA1 and BRCA2 hereditary breast and ovarian cancer
  • Carney complex, caused by pathogenic variants in PRKAR1A gene
  • Carney-Stratakis syndrome, caused by pathogenic variants in SDHB, SDHC, and SDHD genes.

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for ovarian cancer using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variant is identified after analysis of the Gastric cancer panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.


Referral reasons

Genetic testing for gastric cancer is recommended for persons who show one or more of the following features:

  • History of colon or any gastrointestinal cancer
  • Positive family history of gastric cancer and premalignant gastrointestinal conditions
  • Present gastrointestinal conditions and a family history of cancer
  • History of chronic and complex gastrointestinal condition.

     


Test utility

Sequencing, deletion/duplication of gastric cancer related genes should be performed in all individuals suspected of having gastric cancer. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of variants, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of gastric cancer, identify at-risk family members, provide information about reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.