The Penn GI Cancer Genetics Program is at the nexus of treatment and genetic research for inherited GI cancers, including gastric and pancreatic cancers, and the heritable colorectal cancer and polyposis syndromes.
Given the breadth of the Program, this article will focus on the latter, for which the Program has developed a series of unique protocols. Of note, however, in gastric cancer genetics is a recent grant awarded to Program Director Bryson Katona, MD, PhD, to better define the gastric cancer risks associated with the CTNNA1 gene. Other major areas of research involve pancreatic cancer early detection, including endoscopic ultrasound-based surveillance in carriers of BRCA1,BRCA2,PALB2,ATM gene mutations as well as those with a strong family history of pancreatic cancer without a known genetic mutation.
About the Heritable CRCs
A focus of the GI Cancer Genetics Program at Penn GI, the hereditary colorectal cancers (CRCs) represent a collection of cancer predisposition syndromes with specific mutations leading to an increased risk of colorectal cancer. The most common of the heritable CRC syndromes includes Lynch Syndrome, previously known as hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis. Other less frequent CRC predisposing syndromes include the hamartomatous and serrated polyposis syndromes.
Familial adenomatous polyposis (FAP) is distinguished by the presence of numerous small adenomatous polyps throughout the colon.
Familial adenomatous polyposis (FAP) is a disorder distinguished by the presence of hundreds to thousands of small adenomatous polyps throughout the colon. Lynch syndrome is identified with the early onset of colon cancer, as well as a plethora of malignancies originating in organs outside the colon, including the endometrium, ovary, kidney, bladder, ureter, and skin.
Both FAP and Lynch Syndrome are autosomal dominant, and their causative genes have been well described. Lynch syndrome is caused by mutations in genes that affect DNA mismatch repair; FAP has its origin in a defect in the adenomatous polyposis coli (APC) gene.
Managing the Heritable CRCs at Penn Medicine: Diagnosis
Among the objectives of Penn's GI Cancer Genetics Program is to better define the management and surveillance of the heritable CRC syndromes through research and outreach to the affected population.
Given the seriousness of the disorders, multidisciplinary care is extremely important for patients at risk for the inherited CRC syndromes and those previously diagnosed, says Dr. Katona, a practicing gastroenterologist and leading researcher in the field.
"Care for heritable CRC patients must be comprehensive," Dr. Katona observes. "It begins with genetic testing to confirm diagnosis of the syndromes and is followed by gastrointestinal screening, which involves colonoscopy and upper endoscopy."
Precise diagnosis is the key to the development of a comprehensive cancer screening, risk-reduction and management plan for individuals with FAP and Lynch Syndrome, and at-risk relatives. This screening is then the stepping stone to further care, often involving colorectal surgical resection in conjunction with the Colon and Rectal Surgery division.
A number of considerations must converge prior to ordering genetic testing, however, including type of genetic testing offered, timing of genetic testing, and family planning considerations related to this testing.
At Penn, GI cancer genetic risk evaluation begins with an appointment with Dr. Katona and one of the licensed-certified genetic counselors from the Abramson Cancer Center who are associated with the GI Cancer Genetics program, and who specialize in the needs of the heritable CRC population.
Surveillance
Studies have suggested that surveillance can be sporadic in patients with the heritable CRC syndromes. This may be because a lack of expert consensus for interval, age of initiation, and method of surveillance for these syndromes. A part of the research mission for the Penn GI Cancer Genetics Program, therefore, has involved working to better define surveillance for this high-risk populations.
All individuals with Lynch syndrome at Penn GI, for example, currently receive upper GI surveillance starting around age 30 with mucosal biopsies of the gastric antrum and body. Follow-up occurs at a 1-2 year surveillance interval, with upper endoscopy performed concurrently with a lower GI surveillance procedure. Upper endoscopy, as well as the surveillance interval, are supported in Lynch syndrome by the findings of a 2020 study led by Dr. Katona.
"When our study was published in 2020, it was the largest study to date looking at the role of upper gastrointestinal surveillance in Lynch syndrome. We found that upper gastrointestinal surveillance was able to identify early stage gastric and duodenal cancers in this high-risk population, and the study provided clear support for performing upper gastrointestinal surveillance in all patients with Lynch syndrome."
Penn GI Cancer Genetics: Distinguishing Features
In addition to advances in diagnosis and surveillance, the GI Cancer Genetics Program is differentiated by factors thought to contribute to improved outcomes in the heritable GI cancers, including the presence of interdisciplinary tumor boards, the clinical experience of its practitioners and the volume of high-risk patients seen with hereditary cancer predisposition. Further, Penn GI, the Division of Hematology Oncology, and Abramson Cancer Center are actively involved in identifying disparities in the delivery of GI cancer genetic counseling and testing for high-risk patients to ensure that all individuals have access to these important services.
Translational Research at the Penn GI Cancer Genetics Program
As previously noted, a part of the Penn GI Cancer Genetics program's mission is to integrate basic science research with clinical and translation research to lead to innovations in disease management in these high-risk patients. These efforts are greatly enhanced by the presence of the program's Gastrointestinal Cancer and Polyposis Registry, as well as the Colorectal Cancer biobank and the Lynch Syndrome biobank.
The purpose of the Gastrointestinal Cancer and Polyposis Registry as well as the Colorectal Cancer biobank is to support colon cancer research across Penn. The Program's Lynch Syndrome biobank includes blood and stool samples as well as colon tissue samples, from nearly 200 patients, which are actively utilized by multiple investigators across Penn.
According to Dr. Katona, enrollment in clinical studies is incredibly important for moving the field forward, and enrollment in these studies is offered to many patients seen in the GI Cancer Genetics Program.
Among these trials is a biosample acquisition study known as the Lynch syndrome mucosal Immune and MicroBiOme initiative (or LIMBO) conducted in collaboration with E. John Wherry, PhD, Chair, Department of Systems Pharmacology & Translational Therapeutics and Co-Director, Parker Institute for Cancer Immunotherapy. LIMBO and a partner trial, the Lynch Syndrome Immune Profiling Project (or LIP2) are focused on trying to characterize and understand the implications of the peripheral and mucosal immune systems in Lynch syndrome.
Colon cancer tissue samples are also gathered, Dr. Katona attests, and used to collaborate with laboratory researchers across Penn, including a pilot study to develop a vaccine for colorectal cancer with Kim Reiss Binder, MD, of the Division of Hematology Oncology.
Referral for individuals with Heritable CRC Syndromes
Patients may be referred to the GI Cancer Genetics Program for evaluation of inherited CRC syndromes on the basis of family history of these conditions or a recent diagnosis in the patient's family. Regardless of the patient's known medical history, genetic evaluation and testing are warranted when there is a family history of a known disease-causing variant in an adenomatous polyposis or Lynch syndrome gene in a relative, as well as when there is a family history of suspected polyposis syndrome or other CRC risk syndrome without the ability to test the affected relative.
For more information about evaluative referrals to the GI Cancer Genetics Program, please contact: 215-349-8222 or GI Cancer Genetics webpage