Are you aware of the "hereditary tumor susceptibility syndrome" associated with an increased risk of stomach cancer?

The NCCN Clinical Practice Guidelines: Gastric Cancer (Version 2.
2022) points out that although most gastric cancers are considered sporadic, it is estimated that 3% to 5% of them are related
to hereditary tumor susceptibility syndromes.
For patients with a known high risk of hereditary tumor susceptibility syndrome, referral to a cancer genetics specialist
is recommended.

In this paper, the hereditary tumor susceptibility syndrome associated with an increased risk of gastric cancer is summarized
.

Hereditary diffuse gastric cancer

Hereditary gastric cancer accounts for about 1% to 3% of all gastric cancer cases, including at least three major syndromes: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal gastric polyposis (GAPPS), and familial intestinal gastric cancer (FIGC), of which HDGC is the first recognized hereditary gastric cancer syndrome
.

HDGC is an autosomal dominant genetic syndrome characterized
by highly invasive diffuse gastric cancer.
According to the literature, germline truncation mutations
of the tumor suppressor gene CDH1 (encoding the intercellular adhesion protein E-cadherin) have been found in 30% to 50% of HDGC patients' families.
The average age of diagnosis is 37 years, and it is estimated that by age 80, the lifetime risk of stomach cancer is 67% for men and 83%
for women.
In a recent analysis of 75 families with CDH1-pathogenic mutations, it was speculated that cumulative incidence of gastric cancer at age 80 was estimated at 42% and 33% in men and women, respectively
, indicating that the lifetime risk of gastric cancer in CDH1 mutation carriers may be significantly lower than previously reported.

For carriers of CDH1 germline truncation mutations, prophylactic total gastrectomy (without D2 lymph node dissection)
is recommended between the ages of 18 and 40 years.
Prophylactic gastrectomy before the age of 18 years is not recommended, but gastrectomy
may be considered in some patients, particularly those with family members diagnosed with gastric cancer before the age of 25 years.
Baseline endoscopy is required prior to prophylactic total gastrectomy
.
Carriers of the CDH1 mutation who choose not to undergo prophylactic total gastrectomy should undergo upper gastrointestinal endoscopic screening and multiple random biopsies
every 6 to 12 months.
However, available evidence suggests that endoscopy may not adequately detect prodromal lesions
of diffuse gastric cancer.
In addition, women with CDH1 germline truncated mutations are at higher
risk of breast cancer.
For CDH1 mutation carriers without a strong family history of HDGC, genetic counseling
with multidisciplinary review is recommended.

More than 40% of patients with HDGC do not carry the CDH1 mutation, indicating the presence of other susceptibility genes
.
Recent studies have shown that the known breast cancer susceptibility gene PALB2, the adapter protein that encodes BRCA2 function, promotes susceptibility
to familial gastric cancer.
In a large genomic study of cancer susceptibility variants, functional deletion mutations in five different germlines of PALB2 were found in patients with gastric adenocarcinoma
.
In a total exome sequencing study of the CDH1 mutation uncorrelated HDGC family, multiple missing variants
of PALB2 were confirmed.
In addition, PALB2 loss variation in the HDGC family was found to be more common
than in the general population.
These results suggest that PALB2 plays a role in HDGC
.
However, more evidence is needed to justify
routine PALB2 genetic testing in HDGC family members without CDH1 mutations.
Lynch syndrome Lynch syndrome
(LS), also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant hereditary tumor caused
by embryonic mutations in the mismatch repair gene (MMR).
The disease is mainly manifested as colorectal cancer (CRC), and is accompanied by other extraintestinal tumors at the same time or progressively, such as endometrial cancer, stomach cancer, ovarian cancer, etc
.

Lynch syndrome is caused
by germline mutations in four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2).
Epithelial cell adhesion molecule (EPCAM) gene deletions have also been linked
to Lynch syndrome.
Stomach cancer is the second most common extracolon cancer in people with Lynch syndrome (after endometrial cancer).

These patients have a 1% to 13% risk of stomach cancer (mainly bowel type) and occur earlier than in
the general population.
Asians are at higher risk than Westerners
.
In a recent study of data from 3828 carriers of Lynch syndrome-related mutations, it was found that personal history of gastric cancer was independently associated
with the number of people in men, older age, those with mutations in MLH1 or MSH2, and the number of first close relatives with gastric cancer.

Esophageal gastroduodenoscopy (EGD) and enlarged duodenoscopy (distal duodenum or jejunum) may be used as screening strategies
for some individuals or Asian Americans.
Juvenile polyposis syndrome Juvenile polyposis syndrome (JPS) is a rare autosomal dominant genetic syndrome
characterized by the presence of multiple juvenile polyps along the gastrointestinal tract and associated
with an increased risk of gastrointestinal cancer.
JPS is derived from a germline mutation
in the SMAD4 or BMPR1A genes.

The lifetime risk of developing gastrointestinal cancer in patients with JPS varies by mutation type and ranges
from 9% to 50%.
When the upper gastrointestinal tract is affected, an individual JPS has a 21% lifetime risk of stomach cancer, mainly in carriers
of the SMAD4 mutation.
Screening with EGD may be considered, starting with teenage and re-examined annually from the teenage age if polyps are found; If no polyps are found, they are reviewed every 2 to 3 years
.
Black Spot Polyp Syndrome Black Spot Polyp Syndrome
(PJS) is an autosomal dominant syndrome caused by a germline mutation in the STK11 tumor suppressor gene and is seen in 30% to 80% of patients
.
PJS is characterized by cutaneous mucosal pigmentation and gastrointestinal polyposis and is associated
with an increased risk of developing gastrointestinal cancer.

PJS individuals have a 29% lifetime risk of stomach cancer, and their risk of developing other cancers is also increased
.
Screening with EGD may be considered, starting in late adolescence and then retesting every 2 to 3 years based on gastric polyp load
.
Familial adenomatous polyposis familial adenomatous polyposis (FAP) is an autosomal dominant colorectal cancer syndrome caused by
a germline mutation in the E.
coli (APC) gene for chromosome adenomatous polyposis
5q21.
FAP is characterized by the progression of adenomatous colorectal polyps to colorectal cancer
at the age of 35 to 40 years.
Upper gastrointestinal polyps in the stomach, duodenum, and peri-ventral areas are the most common extracolonic manifestations of FAP
.
Most gastric polyps (about 90%) are nonadenomatous benign fundus polyps and are seen in about 50% of patients with
FAP.
Gastric adenomatous polyps (which can cause stomach cancer) account for 10%
of the diagnosed gastric polyps in these patients.
FAP individuals have a lifetime risk of stomach cancer ranging from 1% to 2%.


There is no clear evidence to support specific recommendations
for gastric cancer screening in the FAP population.
However, given the increased risk of duodenal cancer, the stomach
should be examined at the same time as duodenoscopy.
If possible, non-fundus polyps in the stomach should be treated
endoscopically.
Patients whose polyps cannot be removed endoscopically (e.
g.
, invasive carcinoma) should be referred for gastrectomy
.
Baseline EGD and lateral endoscopy are recommended at 25 to 30 years of age, and follow-up
based on duodenal polyp load.

In addition to the more common syndromes discussed above, there are many less common inherited cancer susceptibility syndromes that are also associated
with the risk of developing stomach cancer.
Ataxia-telangiectasia, Bloom syndrome, hereditary breast and ovarian cancer syndrome, Lee-Fomeni syndrome, pigment-dry skin disease and Couden syndrome have all been reported to increase
the risk of stomach cancer.
However, there is insufficient evidence for gastric cancer screening in these patients and is therefore not recommended at this time
.

References: 1.
FENG Wei,ZHENG Hongqun.
Research progress and diagnosis and treatment of hereditary diffuse gastric cancer.
International Journal of Genetics,2018,41(1):56-60.
2.
NCCN Clinical Practice Guidelines: Gastric Cancer (Version 2.
2022)-Chinese Edition 3.
ZHAO Licong, FANG Jingyuan.
Research advances in colorectal cancer associated with Lynch syndrome[J] .
Chinese Journal of Internal Medicine, 2022, 61(9): 1080-1084.
4.
Feng Jun, Geng Yiting, Zhou You, et al.
Diagnosis and treatment norms and progress of familial adenomatous polyposis [J] .
Chinese Journal of Internal Medicine, 2022, 61(8): 959-964.