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Researchers identify age-associated risks for gastric, breast cancers with CDH1 mutations
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Age-associated risks for breast and gastric cancers in individuals who harbor CDH1 mutations in families who meet criteria for hereditary diffuse gastric cancer syndrome may improve genetic counseling of unaffected carriers, according to study results.
Samantha Hansford, MSc, of the Center for Translational and Applied Genomics of the British Columbia Cancer Agency, and colleagues sought to determine risk estimates for gastric and breast cancers in individuals who harbor CDH1 mutations, a gene commonly mutated in families with hereditary diffuse gastric cancer syndrome. Researchers also sought to identify germline mutations other than CDH1 in these families.
The analysis included 183 index cases with hereditary diffuse gastric cancer defined according to International Gastric Cancer Linkage Consortium criteria.
Thirty-four of the index cases harbored 31 distinct pathogenic CDH1 mutations, 14 of which were novel and 17 of which had been previously reported.
Researchers evaluated data from these CDH1 mutation-positive families, as well as additional mutation-positive families from other cohorts. The analysis included a total population of 75 families comprised of 3,858 individuals.
Hansford and colleagues used these data to calculate the cumulative incidence of gastric and breast cancers in individuals by age 80 years.
The cumulative incidence of gastric cancer in the population was 70% (95% CI, 59-80) for males and 56% (95% CI, 44-69) for females. The risk for breast cancer among females in the cohort was 42% (95% CI, 23-68).
Researchers then evaluated data from 144 individuals within families who met hereditary diffuse gastric cancer syndrome criteria but who did not harbor CDH1 mutations. Sixteen of these individuals (11.1%) harbored candidate mutations, including mutations within high- and moderate-penetrance genes such as CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MRS1 and PALB2.
CTNNA1 mutations may be similar to the genetic and functional significance of CDH1 mutations, and screening for CTNNA1 may be warranted in prospective families of hereditary diffuse gastric cancer syndrome, the researchers wrote.
“To our knowledge, this study represents the most robust and thorough description of hereditary diffuse gastric cancer-novel CDH1 mutations and the penetrance in CDH1 mutation carriers to date,” Hansford and colleagues wrote. “These data should assist in the genetic counseling and management of at-risk individuals from CDH1-positive hereditary diffuse gastric cancer families.”
Data on the incidence of gastric and breast cancers in this population should be used to update guidelines, James M. Ford, MD, of the division of oncology in the departments of medicine and genetics at Stanford University School of Medicine, wrote in an invited commentary.
“These updated risk assessments should be considered the new standard for genetic counseling and will be included in the next International Gastric Cancer Linkage Consortium guidelines,” Ford wrote. “Current guidelines suggest breast cancer screening using annual MRI starting at age 30 years and consideration of prophylactic total gastrectomy 5 years younger than the youngest case in the family, with endoscopic screening recommendations remaining poorly defined.” – by Alexandra Todak
Disclosure: The researchers report research funding from the Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at the Canadian Institutes of Health Research and the Portuguese Foundation for Science and Technology. Ford reports no relevant financial disclosures.
Perspective
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David H. Ilson, MD, PhD
Gastric cancer, a significant public health problem in East Asia, arises from a familial predisposition in 10% or fewer cases. The association of an increased risk for gastric cancer with both polyposis and nonpolyposis colorectal cancer syndromes, Peutz-Jeghers syndrome and BRCA-related breast cancer was previously recognized. In the past decade, a rare syndrome of hereditary diffuse gastric cancer (HDGC) was identified in families carrying autosomal dominant mutations of the E-cadherin or CDH1 gene.Hansford and colleagues now report the results of an international collaborative effort studying one of the largest series of families with HDGC, evaluating not only CDH1 mutation but also other potential cancer susceptibility genes in CDH1 mutation-negative cases. Only 34 (19%) of 183 index cases were identified to harbor a CDH1 mutation, a lower frequency than in previously reported smaller series. A high degree of heterogeneity for mutations was observed, with 31 distinct CDH1 mutations — including 14 that were novel and previously unreported. Other potentially pathogenic mutations were documented in 16 cases of 144 probands (11%).
This study deepens our understanding of the underlying genetic causes of HDGC, indicating less common than expected but highly heterogeneous presence mutations of CDH1, and other potential pathogenic mutations in a small percentage of cases. The failure to detect diagnostic mutations in high-risk families, and what the authors report as the presence of mutations in families who would not meet clinical criteria to be defined as a high-risk family for HDGC, underscore the need to appreciate the syndrome of HDGC. The impact clinically is the referral for prophylactic gastrectomy, considered the procedure of choice in CDH1 mutation carriers given the authors’ reported 40% risk for males to develop gastric cancer and the 63% risk for women to develop gastric cancer, and the surveillance required in women given the increased risk of developing lobular breast cancer. Consideration of appropriate screening endoscopy in individuals carrying other pathogenic mutations, or in high-risk families based on clinical criteria in the absence of a definable mutation, also needs to be incorporated into clinical practice. Given the contribution of somatic CDH1 mutation in the genesis of sporadic gastric cancer, understanding the biology of mutations driving HDGC likely will contribute to future development of therapeutic strategies and potentially cancer-preventive strategies in high-risk families.
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Philip Agop Philip, MD, PhD, FRCP
The report by Hansford and colleagues improves our understanding of hereditary diffuse gastric cancer syndrome and advances our thinking of the underlying genetic abnormalities. Specifically, CDH1 mutations are not the sole genetic abnormality and, as such, the study expands the genetic definition of hereditary diffuse gastric cancer. The report also improves our ability to estimate the probabilities of age-associated risk for developing gastric cancer or breast cancer in CDH1 mutation carriers.The relatively high incidence of gastric and breast cancers in subjects with these mutations and the improved knowledge on the types of genetic mutations emphasize the need to look for individuals who may carry these mutations and refer them for genetic counseling. However, the optimal surveillance strategy for individuals at risk for gastric cancer remains to be defined. Additional gene mutations are likely present in hereditary diffuse gastric cancer, underscoring the need for studies based on large-scale international collaborations using broader whole-genome analyses.
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