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Kirsten N. Kangelaris, MD; Stephen B. Gruber, MD, PhD, MPH

JAMA. 2007;297:(doi:10.1001/jama.297.21.2410).

Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant cancer susceptibility syndrome characterized by early onset diffuse gastric cancer and lobular breast cancer.¹ The clinical presentation of this particular form of familial gastric cancer was described more than 40 years ago² and the phenotype can be dramatic. One descendant of the original Maori kindred from New Zealand died of gastric cancer at the age of 14 years; more than 25 of his relatives have succumbed to cancer.³ In a Michigan family with HDGC, 1 family member died from gastric cancer at the age of 17 years, and numerous other family members died of metastatic disease before reaching age 50 years.⁴ Fortunately, genetic testing has already transformed the care of families with HDGC, and the tragic outcomes in these 2 representative families can now largely be avoided. Prophylactic gastrectomy has the potential to eliminate the risk of gastric cancer in gene carriers,^5-7 while surveillance and other strategies for breast cancer prevention offer protection to women at risk.⁸

In this issue of JAMA, Kaurah and colleagues⁹ report a large family-based study that offers insight into the distribution and clinical meaning of the mutations in the E-cadherin (CDH1) gene that cause HDGC. In one sense, this study simply extends prior work showing that mutations causing HDGC span the entire coding region of the gene¹⁰ and confirms that the lifetime risk of cancer among gene carriers is very high.¹¹ In the present study by Kaurah et al, the authors estimate that the cumulative risk of gastric cancer in 2 of their largest families is approximately 40% in men and approximately 60% for women, with a corresponding 52% risk of breast cancer. These findings represent slightly lower risks of gastric cancer and higher risks of breast cancer than reported in a previously published meta-analysis,¹¹ but the risk estimates from both studies overlap and it is clear that the absolute risks are high. Perhaps the most valuable contributions of the present study are the data illustrating how difficult it can be to determine whether a change in a gene sequence is a pathogenic mutation or a benign polymorphism, and the data emphasizing how the same mutation in the same gene can arise by either common ancestry or chance.

The full story starts in New Zealand, spans the globe, and ends in Newfoundland, with families and investigators from 6 countries in 3 continents contributing to the present study. Guilford and colleagues³ first discovered that germline mutation of CDH1 causes HDGC in their 1998 study of 3 separate families in New Zealand.³ Other groups quickly confirmed that germline mutations in CDH1 were responsible for HDGC in families of diverse ethnic origins.^{3, 12-13} In the study by Kaurah et al,⁹ a multinational group of investigators summarize the clinical and genetic findings in 38 families with HDGC ascertained between 2004 and 2006, nearly doubling the published world experience. Some of the findings are entirely consistent with the earlier literature. In this new series, the sensitivity of detecting CDH1 mutations in families meeting criteria for HDGC is 39%, with 15 mutations detected in 38 families (clinical criteria as defined by the International Gastric Cancer Linkage Consortium¹⁴). The sensitivity increased to 54% (14 mutations in 26 families) when more stringent diagnostic criteria were applied that considered only those families defined by at least 2 gastric cancer cases with 1 or more diffuse-type gastric cancer cases diagnosed before age 50 years. Thus, the sensitivity has not changed substantially from the corresponding sensitivity of 31% and 48% published by this group in 2004.¹⁰

The distribution and broad spectrum of CDH1 mutations also are similar to a previous report.¹⁰ Genetic testing for CDH1 is arduous because of the relatively large size of the gene, broad distribution along the entire coding sequence of CDH1, and heterogeneous mutation spectrum, which includes point mutations, deletions, and insertions.¹⁵ Until the present study, almost all of the more than 50 germline CDH1 mutations reported have been novel. Among those mutations identified more than once, none appeared to represent recognizable founder mutations.^16-18 In the study by Kaurah et al⁹ recurrent mutations accounted for 54% of all mutations found. This proportion is higher than the 10% recurrent mutations previously suggested in the literature but that is to be expected as evidence from genetic testing accumulates. So how difficult is it to detect mutations, and why do recurrent mutations arise?

Mutation detection is not easy, and even when mutations are discovered, they are not always easy to interpret. One strength of the study by Kaurah et al⁹ is careful attention to the functional significance of sequence variation. It is fairly typical to use computational approaches to predict whether a sequence variant is likely to cause disease or simply represents meaningless variation. Ideally, experimental evidence would confirm that the sequence variant actually alters the function of the protein, and that is exactly what Kaurah et al have demonstrated. Cell invasion assays and splicing assays characterize the mutations quite convincingly. However, the sensitivity of genetic testing, even when conducted as carefully as in this study, is still only 50% in the best of circumstances. Therefore, the conclusions are that either undiscovered genes are contributing to HDGC or cryptic mutations of CDH1 are very difficult to identify. This serves as a useful reminder of the cautionary tale of relying exclusively on sequencing to detect mutations, as has been learned in BRCA1 or BRCA2. Some mutations, like gene dosage mutations caused by loss of 1 allele, are simply not detectable by sequencing alone.¹⁹

The second novel contribution of this study by Kaurah et al⁹ is the elegant characterization and analysis of recurrent mutations. Are these the result of independent CDH1 mutational events or common ancestry? The answer turns out to be both. To answer this question the investigators used haplotype analysis to determine whether the same exact mutation arose multiple different times in human history. Haplotype analysis shows more than just the mutation: it shows the similarity of the neighboring chromosomal region that harbors the mutation. In some respects, haplotype analysis provides a view of the mutation in its chromosomal context, somewhat like a high-resolution satellite view of a house on Earth. Zoom out a little, and it becomes apparent whether the view reveals the exact same house (eg, mutation) or an identical house in the same neighborhood on a parallel street.

For example, 3 families reported in this study have the same CDH1 A634V mutation, which means that valine is substituted for alanine at the 634rd amino acid in the protein. Haplotype analysis shows that 2 Portuguese families with this mutation must be distantly related because they both share the exact same mutation on the exact same piece of DNA. The third family is English, and they carry the exact same mutation. However, the surrounding DNA is different, indicating that their mutation arose independently of the Portuguese mutation. Similarly, 2 other families (including 1 of Norwegian/Swedish descent) have an identical splicing mutation and also share a common haplotype, while a third family from Brazil has the same mutation in a completely different context. In Newfoundland, haplotype analysis shows that a recurrent mutation is actually a founder mutation, or an ancestral mutation that accounts for a relatively large distribution of a disease in a specific population. Whether this founder mutation accounts for the higher incidence of gastric cancer that is observed in Newfoundland compared with the rest of Canada²⁰ remains quite speculative but it does emphasize the fact that researchers are increasingly recognizing that, in terms of some genetic mutations, it is a small world after all.

The value of studies like the one by Kaurah et al⁹ is that these investigations help clinicians understand and manage HDGC with more precision, help families understand the risks accompanying a mutation in CDH1, and help population geneticists better understand the distribution of recurrent mutations in CDH1. It is clear that not all families with the same mutation are related to one another, but all of these families are already beginning to recognize that the threshold of preventive molecular medicine has arrived and that the future of HDGC will not resemble the past.

AUTHOR INFORMATION
Corresponding Author: Stephen B. Gruber, MD, PhD, MPH, Departments of Internal Medicine, Epidemiology, and Human Genetics, University of Michigan, Ann Arbor, MI 48105 (sgruber{at}umich.edu).

Published Online: June 3, 2007 (doi:10.1001/jama.297.21.2410).

Financial Disclosures: None reported.

Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.

Author Affiliations: Departments of Internal Medicine (Drs Kangelaris and Gruber), Epidemiology (Dr Gruber), and Human Genetics (Dr Gruber), University of Michigan, Ann Arbor.

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