PALB2 as a familial gastric cancer gene: is the wait over?
Authors: Luis G Carvajal-Carmona
Journal: The Lancet. Gastroenterology & hepatology (2018)

Gastric cancer is the third leading cause of cancer-related mortality, accounting for more than 730 000 deaths worldwide each year.1Karimi P Islami F Anandasabapathy S Freedman ND Kamangar F Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention.Cancer Epidemiol Biomarkers Prev. 2014; 23: 700-713Crossref PubMed Scopus (1084) Google Scholar The prognosis of patients with gastric cancer is dismal because most gastric tumours are diagnosed in late stages when 5-year survival is less than 20%.1Karimi P Islami F Anandasabapathy S Freedman ND Kamangar F Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention.Cancer Epidemiol Biomarkers Prev. 2014; 23: 700-713Crossref PubMed Scopus (1084) Google Scholar Whereas gastric tumours with intestinal histologies are linked to a history of Helicobacter pylori-associated gastritis, the natural history of diffuse gastric cancers is less well understood.1Karimi P Islami F Anandasabapathy S Freedman ND Kamangar F Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention.Cancer Epidemiol Biomarkers Prev. 2014; 23: 700-713Crossref PubMed Scopus (1084) Google Scholar New tools for the prevention and early detection of early gastric cancer are needed to improve survival outcomes. Around one in ten patients with gastric cancer report a family history of malignancy, suggesting an underlying genetic predisposition.1Karimi P Islami F Anandasabapathy S Freedman ND Kamangar F Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention.Cancer Epidemiol Biomarkers Prev. 2014; 23: 700-713Crossref PubMed Scopus (1084) Google Scholar Thus, genetic information could be used for gastric cancer prevention. Until recently, CDH1 was the only known gene associated with familial gastric cancer.2Guilford P Hopkins J Harraway J et al.E-cadherin germline mutations in familial gastric cancer.Nature. 1998; 392: 402-405Crossref PubMed Scopus (1373) Google Scholar CDH1 mutations frequently cause hereditary diffuse gastric cancer syndrome, and detection of mutations in this gene is routinely used for risk assessment and disease management.1Karimi P Islami F Anandasabapathy S Freedman ND Kamangar F Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention.Cancer Epidemiol Biomarkers Prev. 2014; 23: 700-713Crossref PubMed Scopus (1084) Google Scholar, 2Guilford P Hopkins J Harraway J et al.E-cadherin germline mutations in familial gastric cancer.Nature. 1998; 392: 402-405Crossref PubMed Scopus (1373) Google Scholar However, more than 40% of families with hereditary diffuse gastric cancer syndrome do not carry CDH1 mutations, suggesting the existence of additional predisposing genes.3Hansford S Kaurah P Li-Chang H et al.Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond.JAMA Oncol. 2015; 1: 23-32Crossref PubMed Scopus (415) Google Scholar, 4van der Post RS Vogelaar IP Carneiro F et al.Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers.J Med Genet. 2015; 52: 361-374Crossref PubMed Scopus (378) Google Scholar In the past 3 years, our group and others have suggested that mutations in homologous recombination DNA repair genes, such as PALB2, probably explain a substantial proportion of inherited gastric cancers.3Hansford S Kaurah P Li-Chang H et al.Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond.JAMA Oncol. 2015; 1: 23-32Crossref PubMed Scopus (415) Google Scholar, 5Sahasrabudhe R Lott P Bohorquez M et al.Germline mutations in PALB2, BRCA1, and RAD51C, which regulate DNA recombination repair, in patients with gastric cancer.Gastroenterology. 2017; 152: 983-986Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar The study by Eleanor Fewings and colleagues6Fewings E Larionov A Redman J et al.Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study.Lancet Gastroenterol Hepatol. 2018; (published online April 26.)http://dx.doi.org/10.1016/S2468-1253(18)30079-7Summary Full Text Full Text PDF PubMed Scopus (63) Google Scholar in The Lancet Gastroenterology & Hepatology further supports a role for PALB2 in predisposition to hereditary gastric cancer. To identify new gastric cancer-associated genes, the investigators performed whole-exome sequencing in 22 families with hereditary diffuse gastric cancer syndrome that had previously tested negative for pathogenic variants in CDH1. Exome data from affected family members was used to prioritise candidate genes with predicted loss-of-function variants using interaction analyses. A cluster of DNA repair genes, which included known cancer-associated genes such as MSH2 and PALB2, was identified as being significantly enriched for loss-of-function variants. Subsequent analyses of this cluster provided evidence of co-segregation of loss-of-function variants with disease in six (27%) of the 22 families. A frameshift PALB2 variant was identified in one family, and loss-of-function variants in both ATR and NBN were identified in another family. RECQL5 mutations were identified in two families; two others had variants in MSH2, a gene known to be associated with Lynch syndrome.7Lynch HT Snyder CL Shaw TG Heinen CD Hitchins MP Milestones of Lynch syndrome: 1895–2015.Nat Rev Cancer. 2015; 15: 181-194Crossref PubMed Scopus (456) Google Scholar Tumour analyses in the individuals with MSH2 variants did not reveal microsatellite instability or loss of mismatch repair protein expression (both hallmarks of Lynch syndrome7Lynch HT Snyder CL Shaw TG Heinen CD Hitchins MP Milestones of Lynch syndrome: 1895–2015.Nat Rev Cancer. 2015; 15: 181-194Crossref PubMed Scopus (456) Google Scholar), suggesting that these variants were either non-pathogenic or that a new mechanism leads to gastric cancer in these families. To exclude a possible environmental cause, the family members were assessed for history of H pylori infection, the strongest known risk factor for gastric cancer,1Karimi P Islami F Anandasabapathy S Freedman ND Kamangar F Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention.Cancer Epidemiol Biomarkers Prev. 2014; 23: 700-713Crossref PubMed Scopus (1084) Google Scholar and most mutation carriers had previously tested negative for the bacteria. The investigators also combined their data with those from two previous reports3Hansford S Kaurah P Li-Chang H et al.Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond.JAMA Oncol. 2015; 1: 23-32Crossref PubMed Scopus (415) Google Scholar, 5Sahasrabudhe R Lott P Bohorquez M et al.Germline mutations in PALB2, BRCA1, and RAD51C, which regulate DNA recombination repair, in patients with gastric cancer.Gastroenterology. 2017; 152: 983-986Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar and found that PALB2 loss-of-function variants were substantially more common in families with hereditary gastric cancer than in the general population. Genetic studies in gastric cancer have lagged behind those in other gastrointestinal cancers, such as colorectal cancer, for which several susceptibility genes have been reported.8Carvajal Carmona LG Tomlinson I The hunting of the snark: whither genome-wide association studies for colorectal cancer?.Gastroenterology. 2016; 150: 1528-1530Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar The study of gastric cancer genetics is difficult in part because the high mortality makes large family studies unfeasible. Furthermore, dissimilar to colorectal cancer, gastric cancer is more commonly diagnosed in low-income countries, where research and clinical practice of cancer genetics is limited by funding and the scarcity of medical professionals in the field, among other reasons.9Rastogi T Hildesheim A Sinha R Opportunities for cancer epidemiology in developing countries.Nat Rev Cancer. 2004; 4: 909-917Crossref PubMed Scopus (123) Google Scholar Therefore, the investigators should be commended for these findings. Nevertheless, given the small number of families with PALB2 variants (only ten have been reported thus far), translating these findings into prevention of gastric cancer will require additional research. For example, should cases of familial intestinal gastric cancer be tested for PALB2 variants? The study5Sahasrabudhe R Lott P Bohorquez M et al.Germline mutations in PALB2, BRCA1, and RAD51C, which regulate DNA recombination repair, in patients with gastric cancer.Gastroenterology. 2017; 152: 983-986Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar from our group identified seven individuals with PALB2 mutations, of whom three had intestinal tumours and one had a tumour of mixed histology. Given that hereditary diffuse gastric cancer syndrome includes only cases with diffuse histology, our findings suggest that PALB2 mutations define a unique syndrome with heterogeneous histological types. Further studies focusing on non-diffuse gastric cancer are therefore needed to understand whether PALB2 mutations define a familial gastric cancer syndrome. Germline mutations in PALB2 have already been associated with an increased risk of breast and pancreatic cancer, and hundreds of families are known to have mutations in this gene.10Antoniou AC Casadei S Heikkinen T et al.Breast-cancer risk in families with mutations in PALB2.N Engl J Med. 2014; 371: 497-506Crossref PubMed Scopus (568) Google Scholar It is now important to identify which factors increase the risk of gastric cancer in such families. Both the study by Fewings and colleagues6Fewings E Larionov A Redman J et al.Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study.Lancet Gastroenterol Hepatol. 2018; (published online April 26.)http://dx.doi.org/10.1016/S2468-1253(18)30079-7Summary Full Text Full Text PDF PubMed Scopus (63) Google Scholar and our study5Sahasrabudhe R Lott P Bohorquez M et al.Germline mutations in PALB2, BRCA1, and RAD51C, which regulate DNA recombination repair, in patients with gastric cancer.Gastroenterology. 2017; 152: 983-986Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar found insufficient evidence of a modifier role for H pylori infection in PALB2 mutation carriers, but it is possible that the risk of gastric cancer is affected by PALB2 mutation hotpots, modifier genes, and other unaccounted environmental factors. These questions highlight the need for further research. This emerging body of data provides a compelling case for offering PALB2 testing to families with hereditary gastric cancer that have previously tested negative for pathogenic CDH1 mutations. Given that the tumours of individuals with PALB2 mutations are likely to be deficient in homologous recombination DNA repair (as shown in our study5Sahasrabudhe R Lott P Bohorquez M et al.Germline mutations in PALB2, BRCA1, and RAD51C, which regulate DNA recombination repair, in patients with gastric cancer.Gastroenterology. 2017; 152: 983-986Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar), these individuals could potentially benefit from PARP inhibitor therapies, which might be effective in homologous DNA repair-deficient tumours.11Alexandrov LB Nik-Zainal S Siu HC Leung SY Stratton MR A mutational signature in gastric cancer suggests therapeutic strategies.Nat Commun. 2015; 6: 8683Crossref PubMed Scopus (119) Google Scholar 20 years after the discovery of CDH1, the identification of PALB2 as a new gene potentially associated with familial gastric cancer is of dual importance for both prevention and treatment of gastric cancer. I declare no competing interests. I receive research funding from the National Cancer Institute (R01CA223978 and R21CA199631) of the National Institutes of Health. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing studyThe results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families. Full-Text PDF Open Access