Hereditary diffuse gastric cancer: What the clinician should know

Table 1 Clinical criteria for CDH1 genetic testing (adapted from Fitzgerald et al[11])

≥ 2 diffuse GC cases in 1st or 2nd degree relatives with one < 50 yr of age

≥ 3 diffuse GC cases in 1st or 2nd degree relatives independent of age

Diffuse GC < 40 yr of age, without a family history

Personal or family history of diffuse GC and lobular breast cancer with one < 50 yr of age

GC: Gastric cancer.

Table 2 Summary of non-CDH1 germline mutations in hereditary diffuse gastric cancer

Gene	Mutation	Location	Mutation type	Ethnicity	Ref.	Study type	Frequency	Remarks
CTNNA1	c.76delGA	Chr 5: 138117693	Nonsense	No data	[13]	Family study	1/1 family	Results in a framshift after Arg27 (p.Arg27Thr.fs*17)
MAP3K6	c.598G>T	Chr 1: 27690792	Missense	Canada	[14]	Family study and case series	1/1 family 1/115 cases	Likely pathogenic
MAP3K6	c.620T>G	Chr 1: 27690770	Missense	No data	[14]		No data
MAP3K6	c.2837C>T	Chr 1: 27684750	Silent	No data	[14]		No data	Single nucleotide variant also in Canadian family, likely pathogenic
MAP3K6	c.2872C>A	Chr 1: 27684715	Missense	No data	[14]		No data
MAP3K6	c.2544delC	Chr 1: 27685238 - 27685239	Nonsense	Portugese	[14]		1/115 cases
INSR	c.3937 G>A	Chr 19: 7117279	Missense	Finland	[15]	Family study	1/1 family
FBXO24	c.242G>C	Chr 7: 100187900	Missense	Finland	[15]		1/1 family
DOT1L	c.3437C>T	Chr 19: 2223326	Missense	Finland	[15]		1/1 family

Table 3 Comparison of hereditary cancer syndromes

Condition	Genetic pathology	Lifetime risk of gastric cancer	Histological subtype	Other clinical features
Hereditary diffuse gastric cancer	CDH1 germline and other gene mutations	80%	Diffuse	Association with lobular breast cancer and cleft-lip malformations
Lynch syndrome	Mutations in mismatch repair genes	4.8% in MLH1 carrier 9% in MLH2 carrier[58]	Mainly intestinal-type	Lifetime risk of colon cancer 31%-38%, endometrial cancer 34% and ovarian cancer 20%[59]
Familial adenomatous polyposis	APC germline mutations	Population risk[60]	No data	Malignant extraintestinal tumours rare < 3% (thyroid, pancreas, medulloblastoma)[61]
Li-Fraumeni syndrome	TP53 mutations	14.9%[62]	No predominant subtype	Associated with wide range of early-onset cancers. Includes haematological and solid organ cancers: sarcomas, breast, brain, adrenal and lung cancers
Peutz-Jegher’s syndrome	STK11 mutations	29%[63]	No data	Characteristic mucocutaneous pigmentation commonly around mouth and nose High cumulative lifetime risk of any cancer (85%), most commonly colorectal (50%)[58]
Juvenile polyposis syndrome	SMAD4 or BMPR1A mutations	121%[64]	No data	Also at increased

¹Frequency based on cross-sectional sample rather than lifetime risk from cohort study.