Familial Gastric Cancer: Genetics, Diagnosis, and Management

This article focuses on the diagnosis and management of familial gastric cancer, particularly hereditary diffuse gastric cancer (HDGC). First, existing consensus guidelines are discussed and then the pathology and genetics of HDGC are reviewed. Second, patient management is covered, including surveillance gastroscopy, prophylactic total gastrectomy, and management of the risk of breast cancer.

An army marches on its stomach. —Napoleon Bonaparte 1769–1821

The Bonapartes are probably the most notorious reported gastric cancer family. However, recent analysis of Napoleon’s family history and pathology records challenges the assumption of inherited predisposition. Two hundred years ago, the practice of medicine largely rested on the arts of taking an accurate history and sharp clinical observation. Today, despite the explosion in molecular and genetic knowledge, this is still the case and a meticulous family history remains a cornerstone of diagnosis in familial cancer.

Although hereditary diffuse gastric cancer (HDGC) is relatively rare, sporadic, gastric cancer, it is the fourth most common cancer worldwide. In 1998, germline mutations in the E-cadherin gene ( CDH1 ) were first described in three gastric cancer families from New Zealand. In the year after this discovery, different CDH1 mutations were identified in other gastric cancer families from around the world, culminating in the definition of the first and, to date, only inherited cancer syndrome dominated by gastric cancer, HDGC. Despite extensive mutation searching in other candidate genes, no further mutations have been found in families in which gastric cancer predominates.

Parry Guilford and colleagues identified the mutant CDH1 gene, in part, because the pedigree of the index family (a large Maori family known as Family A) was well documented, permitting an accurate genetic linkage analysis. Forty years before this, in 1964, Dr Ted Jones, a young resident doctor at Tauranga Hospital had published the tragic story of multiple deaths in very young family members from a diffuse type of stomach cancer. In 1965, Pekka Lauren, of the eponymous Lauren Classification, published his seminal work on the different morphologic types of gastric cancer.

Lauren described the distinction between stomach cancers that form glands (eg, cancers of the colonic intestine), which he called the “intestinal type,” and the “diffuse type” in which discohesive malignant cells invade in single files, sheets, or nests of cells without forming a discrete mass. Epithelial-cadherin is a cell-to-cell adhesion molecule that is a central component of the adherens junction. The difference in E-cadherin expression between gastric cancer histotypes was first demonstrated immunohistochemically by Shimoyama and Hirohashi in 1991. Their study showed that in diffuse gastric cancer (DGC) E-cadherin expression was occasionally absent, but more often reduced or abnormal. Subsequently, Becker and colleagues supported this by demonstrating that CDH1 mutations are restricted to sporadic gastric cancers with diffuse morphology.

Later work demonstrated that inactivating E-cadherin mutations are exclusively observed in the diffuse component of mixed gastric carcinomas. In a commentary on this paper and other literature, Chan and Wong highlighted that loss of E-cadherin provides a “plausible explanation” for the divergent morphologic phenotype in lobular versus ductal breast cancer and DGC versus intestinal gastric cancer (IGC). In Newfoundland, Canada, a germline CDH1 mutation was detected in another very large family; however, they were originally identified as a breast cancer family.

This article focuses on the diagnosis and management of familial gastric cancer, particularly HDGC. First, existing consensus guidelines are discussed and then the pathology and genetics of HDGC are reviewed. Second, patient management is covered, including surveillance gastroscopy, prophylactic total gastrectomy, and management of the risk of breast cancer.

Consensus guidelines

In 1999, the first guidelines on diagnosis and management of familial gastric cancer were published by the International Gastric Cancer Linkage Consortium (IGCLC). In New Zealand, because of the particularly young age at which HDGC patients have died, guidelines were needed on the youngest age at which genetic testing, surveillance gastroscopy and prophylactic gastrectomy are recommended. In response, at the 2004 meeting of The New Zealand Familial Gastric Cancer Group (scientists, clinicians, and allied health professionals ) consensus guidelines were established based on collective clinical experience managing these families and the literature. At that time, there were 45 HDGC families reported worldwide, 10 from New Zealand.

In the initial 5 years after CDH1 mutations were described, several key papers were published on genetic counseling, the cumulative risk of gastric and breast carcinoma, prophylactic gastrectomy, early gastric pathology, and surveillance chromogastroscopy.

In 2008, at the seventh workshop of the IGCLC, updated consensus guidelines were generated. Management algorithms have been formulated highlighting the salient management decisions. Now, there are well over 100 HDGC families reported in the literature. The information from the published pedigrees of the first 87 families reported (up to 2008) is summarized in Table 1 including mutation details, number of gastric and breast cancers, known histotypes, age at diagnosis, and cancers at other sites.

Table 1

Germline CDH1 mutations: details of HDGC families and early-onset, sporadic gastric cancer cases-review of published mutations as of March 2008

Family Identification	Ethnicity: Country	CDH1 Mutation	Type	Exon Intron	Mutation Effect	GC (DGC)	Age of GC Cases	Mean Age	Breast (LBC)	Age of Breast Ca	Other Cancers	Reference
C7	ns: North America	3G>C	Non	1	No protein	1 (1)	73	NA	1 (1)	73	—	Suriano 2005
203	European	45insT	ins	1	Truncation	4 (2)	30–67	44	1 (1)	—	3xCo (1xSRC)	Oliveira 2002
—	White	49–2A>C	ss	In 1	—	4 (3)	42, 54, 57, 68	—	1	55	Cr, S, Pr, Bl, Pa, T	More 2007
—	White: UK	49–2A→G	ss	in 1	truncation	6 (4)	34–69	49	nil	—	Lu, Co	Richards 1999
—	ns: Irish	As above	“	“	“	2 (2)	ns	—	ns	—	—	Moran 2005
C220	White	53delC	del	2	truncation	2 (2)	28–48	38	nil	—	Lu, Cx	Humar 2002
—	White: UK	59G→A	non	2	truncation	3 (3)	27–50	38	nil	—	—	Richards 1999
4201	White: USA	70G→T	non	2	truncation	4 (3)	37–46	42	3	39, 39, 46	Leu x2 (45, 66y)	Guilford 1999
—	Japanese	185G→T	mis	3	missense	7 ?	46–72	59	nil	—	—	Shinmura 1999
—	White: USA	187C>T	non	3	truncation	3 (2)	33–85	62	1	—	2x Co, Pr, 2xEn	Gayther 1998
F6	North American	As above	“	“	“	3 (1)	24–52	?	3 (2)	39, 39, 56	LBC 39×2, 1 mixed ca	Suriano 2005
DST	Maori: NZ	190C→T	non	3	truncation	2 (2)	22, 28 + others	?	—	—	—	Guilford 1999
—	White: French	283C→T	non	3	truncation	4 (3)	34, 42, 43, 47	?	2	64, +ns	+ ‘digestive ca’ at 25y	Dussaulax 2001
F1	Unknown	As above	“	“	“	7 (2)	39–76	—	—	—	ns	Kaurah 2007
F2	White	353C>G	mis	3	missense	2 (1)	55, 63	—	nil	—	—	More 2007
—	White: German	372delC	del	3	truncation	4 (2)	15, 37, 38, 58	37	1 (1)	49	—	Keller 1999
F10	Italian	382delC	del	3	—	7 (1)	32, 40, 42, 45, 50, 55, 56	46	2	—	—	Brooks-Wilson 2004
—	White	531+2T>A	ss	In4	truncation	5 (3)	36, 53, 48, 22, 23	—	1	43	4xcleft lip or palate	Frebourg 2006
RS	White: France	586G→T	non	5	truncation	4 (4)	31–55	45	nil	—	—	Guilford 1999
F1	Northern European	687(+1)G>A	ss	Int 5	—	4 (1)	36, 40, 48, 50	43	1	—	—	Brooks-Wilson 2004
—	Caucasian	715G>A	Mis,ss	6	missense	2 (2)	30, 29	—	nil	—	1 mutation +ve alive at 79	More 2007
F2	Filipino	As above	“	“	“	4 (1)	29–33	—	nil	—	—	Karurah 2007
G2	Korean	731A→G	mis	6	missense	7 ?	?38–63	?	nil	—	—	Yoon 1999
215	Finnish	808T>G	mis	6	missense	1	Late 70s	—	nil	—	HPC: 4xPr in 70s	Ikonen 2001
195	Pakistani	832G→A	ss	6	truncation	10 (6)	23–70	37	1	—	—	Oliviera 2002
F26	Northern European	892G→A	mis	7	missense	3 (2)	32, 33, 36	34	—	—	—	Brooks-Wilson 2004
23	Swedish	1003C→T	Non	7	truncation	3 (2)	22, 44, 45	—	1 (0)	51 ductal	Pr x1 86y	Jonsson 2002
F1	North American	As above	“	“	“	8 (2)	25–67	—	nil	—	ns	Suriano 2005
F3	North American	As above	“	“	“	5 (1)	35–55	—	nil	—	ns	Suriano 2005
A	Maori: NZ	1008G→T	ss	7	truncation	28 (9)	14–74	33	2 (1)	Bi lob 43, 49	Co	Guilford 1998
185	European	1018A>G	mis	8	missense	2	35–47	39	—	—	Ovary	Oliviera 2002
F25	Northern European	1064insT	ins	8	—	3 (2)	34, 50, 58	47	nil	—	—	Brooks-Wilson 2004
—	Hispanic	1107delC	del	8	Truncation	3 (2)	27, 48, ?	—	Nil	—	—	More 2007
—	Italian	1118C>T	mis	8	Missense	3 (3)	70, 72, 79	—	nil	—	Co x 1	Roviello 2007
F41	Spanish	1134del8ins5	Del-in	8	—	4 (3)	27, 30, 32 + ^b	—	nil	—	—	Brooks-Wil 2004
SF1	Italian: Brazil	1137G>A	ss	8	ns	3 (2)	18, 28, 37	—	nil	—	Cleft palate, aplasia cutis, partial acrania	Frebourg 2006
F5	White	As above	“	“	“	1 (1) ^b	ns ^b	—	Unknown		—	More 2007
F6	White: Swiss	As above	“	“	“	1 (1)	29	—	1	69	Saliv gland 26y, Co, 2x bilateral lung	More 2007
F3 ^a	unknown	As above	“	“	“	7 (1)	26-44	—	1	—	—	Kaurah 2007
F4 ^a	Sweden or Norway	As above	‘	“	“	3 (2)	37–48	—	nil	—	—	Kaurah 2007
chg72	African American	1137+1G→A	ss	Int 8	truncation	5 (4)	25–58	42	—	—	—	Guilford 1999
F9	Northern European	1212delC	del	9	—	5 (4)	17, 32, 46, 47, 61	41	4	—	—	Brooks-Wilson 2004
F7	Northern European	1226T→C	mis	9	missense	1 (1)	51	51	—	—	SRC colon	Brooks-Wilson 2004
—	Japanese	1243A>C	mis	9	missense	5 (2)	60–63	62	—	—	—	Wang 2003
—	White	1397-92delTC	Del	10	truncation	2 (2)	34, 61	—	1	78	—	More 2007
F5	English	As above	“	“	—	4 (2)	31–82	—	1	62	—	Kaurah 2007
G1001	Korean	1460T→C	mis	10	missense	2 ?	? 42–49	—	nil	—	—	Yoon 1999
PQ036	European	1472-73insA	ins	10	truncation	3 (2)	32–40	35	nil	—	—	Oliviera 2002
F18	Northern European	1476delAG	Del	10	—	2 (1)	32–40	36	nil	—	—	Brooks-Wilson 2004
—	Chinese	1507C>T	non	10	Truncation	ns (1)	—	—	1 (1)	—	Proband DGC and LBC	Jiang 2004
C230	Arab	1565+1G→T	ss	Int 10	truncation	3 (2)	49–56	52	nil	—	—	Humar 2002
1000	White: USA	1588insC	ins	11	truncation	3 (3)	40–63	50	1	—	—	Guilford 1999
—	Spanish	1610delC	del	11	truncation	3 (3)	50, 58, 71	—	1 (1)	<50y	Pr, Co	Rodriguez 2006
—	European or German	1619insG	ins	11	—	1 (1)	29	29	1	49, bilat	Ab, Lu	Keller 2004
F6	Irish	1682insA	ins	11	—	3 (1)	38–52	—	1 (1)	38y + DGC	Note 38y DGC & LBC	Kaurah 2007
C210	African American	1710delT	del	11	truncation	2 (2)	19, 29	24	1	—	Pr	Humar 2002
—	White: USA	1711 insG	Ins	11	truncation	9 ?	30–68	45	nil	—	—	Gayther 1998
F11	Northern European	1711 + 5G>A	ss	In11	—	3 (3)	44–48	45	5 (1)	—	—	Brooks-Wilson 2004
HPc31	Sweden	1774G>A	mis	12	unknown	2	69, 85	—	2	46, 54 (1-ve)	Pr x4 (mean age 69) 1xCo	Jonsson 2002
F2	Northern European	1779insC	Ins	12	—	3 (3)	33–42	37	—	—	—	Brooks-Wilson 2004
—	White: Canada	1792C→T	Non	12	truncation	6 (3)	23–43	31	—	—	—	Gayther 1998
C200	Maori: NZ	As above	“	“	“	3 (1) ?	30–41	35	—	—	Pan	Humor 2002
F5	North America	As above	“	“	“	4 (1)	30–54	—	2	—	—	Suriano 2005
SF2 ^a	Portuguese	1901C→T	mis	12	missense	1 (1)	30	–	nil	—	—	Suriano2003
32SF ^a	Portuguese	As above	“	“	“	2	23, 26	—	nil	—	—	Oliviera 2004
F7	English: no linkage	As above	“	“	“	2 (1)	34, 45	—	1	75	—	Kaurah 2007
F8	Maori	As above	“	“	“	2 (2)	25, 30s	—	nil	—	—	More 2007
F8	Spanish	1913G>A	Non	12	ns	10 (1)	21–59	—	nil	—	—	Kaurah 2007
16, SF4	Northern European	2061delTG	del	13	—	2 (2)	24, 47	36	nil	—	—	Brooks 04+Kaurah
SF9	English or Scottish	As above	“	“	—	3 (1)	37–80	—	2	65?	—	Kaurah 2007
C	Maori: NZ	2095C→T	non	13	truncation	ns	ns	ns	—	—	—	Guilford 1998
F9	Chinese	As above	“	“	“	3 (3)	24, 39, 55	—	—	—	—	More 2007
—	North American	2161C>G	ss	13	—	4 (1)	21–75	—	nil	—	—	Suriano 2005
F10	Unavailable	2164 + 5G>A	ss	In13	—	3 (1)	38–44	—	nil	—	—	Kaurah 2007
F13sf5	Northern European	2195G→A	mis	14	missense	2 (2)	36–70	53	4 (2)	44–86	Note br ca both families	Brooks 04+Kaurah
F11	English: no linkage	As above	“	“	“	3 (2)	32–65	—	4 (1)	40–77	Note br ca both families	Kaurah 2007
F12	Colombian	2245C>T	mis	14	Missense	3 (2)	36–49	—	nil	—	—	Kaurah 2007
F2	North American	2276delG	del	14	—	10 (2)	35–87	—	2 (1)	—	—	Suriano 2005
240	White	2295 + 5G→A	ss	Int 14	truncation	4 (2)	44–52	47	nil	—	—	Humar 2002
F4	Northern European	2310delC	Del	15	—	8 (≥1)	42–79 ^b	61 ^b	1	—	—	Brooks-Wilson 2004
HPC	Swedish	2329G>A	mis	15	n.s	1	74	—	nil	—	Pr x 3 (mean 68y)	Jonsson 2002
F13	English	2343A>T	mis	15	—	2 (2)	51, 63	—	1	ns	—	Kaurah 2007
B	Maori: NZ	2381insC	ins	15	truncation	7 (2)	30 (16–35) ^b	30 ^b	—	—	—	Guilford 1998
—	German	2396C→G	mis	15	—	3 (1m)	41–52 ^b	47 ^b	—	—	—	Keller 2004
SF6, 7 F14,15	Newfoundland founder mutation	2398delC	del	15	ns	29 (7)	25–80	—	16 (4)	41-68	Cox8, Leux3, head or neck2, My, Lu, Br, Es, NHL,	Kaurah 2007
—	Japanese	2494G→A	mis	16	missense	7 (1)	ns	ns	—	—	—	Yabuta 2002
—	White	2440-6C>G	ss	In 15	—	2 (2)	36, ns	—	nil	—	Lu	More 2007
—	Summary	87 families 68 mutations	—	—	30% miss 70% trun	—	5 with case <20y, 9 with case <20–24	—	75 (18)	Youngest case 38y	—	—

	Solitary Cases
—	European: Canada	41delT	del	1	—	1 (1)	30	—	—	—	—	Bacani 2006
C5	North American	1063 del 6	del	8	Truncation	1 (1)	27	—	—	—	—	Suriano 2005
C6	North American	1285 C>T	mis	9	missense	1 (1)	27	—	—	—	—	Suriano 2005
MFW	Not specified	1487del7	del	10	truncation	1 (1)	31	—	—	—	Father: co at 60y	Guilford 1999
g71	African American	1849G→A	mis	12	missense	1	64	—	—	—	—	Ascano 2001
293	African American	1849G→A	mis	12	missense	1	43	—	—	—	Not related to 294	Suriano 2003
294	African American	1849G→A	mis	12	missense	1	43	—	—	—	Not related to 293	Suriano 2003

	Breast Cancer Family
LBC	USA	517insA	ins	4	truncation	nil	—	—	2 (2)	28, 42	Melanomax2, kidney	Masciari 2007