Hereditary gastrointestinal cancers: why genetic counseling matters.

Abstract

Gastrointestinal (GI) cancer, including gastric, pancreatic, and colorectal cancer, is a major cause of death worldwide. A substantial proportion of patients with GI cancer has a familial history, and several causative genes have been identified. Physicians do not always know how to deal with this aspect of their patients’ disease and, in a rapidly evolving landscape, up-to-date guidelines are of utmost importance. In this issue of Annals of Oncology, Stjepanovic et al. [1.Stjepanovic N. Moreira L. Carneiro F. et al.on behalf of the ESMO Guidelines CommitteeHereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 30: 1558-1571Abstract Full Text Full Text PDF Scopus (41) Google Scholar] report ‘Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up’, which was initiated to help physicians screen, diagnose and treat GI cancer patients appropriately. In these guidelines, the authors provide an overview and discuss all the aspects, from genetic testing to long-term follow-up of the principal hereditary GI cancers including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, Peutz–Jeghers syndrome, serrated polyposis syndrome, polymerase proofreading-associated polyposis, NTHL1 adenomatous polyposis, hamartomatous polyposis, hereditary gastric cancers, and hereditary pancreatic cancers. Genetic counseling is emphasized as a major aspect of GI cancer patients’ care. In fact, carriers with these hereditary GI syndromes often harbor several kinds of cancer (not only GI) at an early age, and genetic testing and specific surveillance may save their lives through early detection. In addition, diagnosing a hereditary GI cancer often leads to screening the patients’ relatives and may identify new cases bearing the genetic alteration; in this case, adequately screening is an efficient cancer prevention strategy. Finally, these hereditary GI cancers have led to the identification of genetic and epigenetic alterations that can provide insights regarding the roles played by different cell signaling pathways in carcinogenesis. Studying these carcinogenic pathways, and also the clinical and pathological features of these specific GI cancers, has opened new avenues for the treatment of small subgroups of patients as recently shown with Breast Cancer 2-mutated pancreatic cancer and poly (ADP-ribose) polymerase inhibitors [2.Schrock A.B. Ouyang C. Sandhu J. et al.Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer.Ann Oncol. 2019; 30: 1096-1103Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar], microsatellite instability tumors and immuno-oncologic agents [3.Golan T. Hammel P. Reni M. et al.Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.N Engl J Med. 2019; 381: 317-327Crossref PubMed Scopus (502) Google Scholar]) and fusion-bearing GI cancers and non receptor tyrosine kinase inhibitors [4.Marchiò C. Scaltriti M. Ladanyi M. et al.ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research.Ann Oncol. 2019; 30: 1417-1427Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar]. Gastroenterologists, GI oncologists, and GI surgeons should be familiar with these hereditary syndromes, even though they are not always frequent, nor associated with a high penetrance of GI cancer, and must refer patients to genetic cancer care centers to optimally manage patients and their relatives. If this step is not performed, there will be a clear loss of opportunity for these patients and their families for prevention and early detection. The role of treating physicians in identifying possible carriers is thus crucial. Clinical history, family history of cancer, and tumor genomic phenotype must be used upfront to screen patients with colorectal, gastric, or pancreatic cancer for hereditary cancer syndromes. When looking at technical and logistical aspects, molecular characterization of the genes that are involved in these syndromes has been useful in the development of genetic testing for diagnosis. Currently, however, screening hereditary GI cancers is more often done with large gene panels on academic genetic platforms of with commercial tests. The benefit of commercial tests over what is done on academic well-structured platforms has never been shown. In addition, high costs linked to these commercial tests make them unavailable for the vast majority of patients in the world. Whether the tests are commercial or not, the use of large panels may identify unexpected mutations in some patients. These secondary findings may lead to social and psychological distress and all tested patients need to be informed of what may be the findings of a test using large panels and their consequences before being tested. In most Western European countries, genetic counseling is well-organized and families with different members living in different countries can often be followed up adequately in their respective country. However, this is still not the case in other European and non-European countries, and we will have to, in the future, help these countries to organize their genetic cancer care programs, taking advantage of what has been already done successfully in others, for optimal and complete care of our GI cancer patients.