Accepted Manuscript. Utility of Genetic Testing in Persons with Multiple Colorectal Polyps. Natalia Khalaf, MD, MPH, Niloy Jewel Samadder, MD, MS

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Accepted Manuscript Utility of Genetic Testing in Persons with Multiple Colorectal Polyps Natalia Khalaf, MD, MPH, Niloy Jewel Samadder, MD, MS PII: S1542-3565(19)30259-9 DOI: https://doi.org/10.

1 Accepted Manuscript Utility of Genetic Testing in Persons with Multiple Colorectal Polyps Natalia Khalaf, MD, MPH, Niloy Jewel Samadder, MD, MS PII: S (19) DOI: Reference: YJCGH To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 5 March 2019 Please cite this article as: Khalaf N, Samadder NJ, Utility of Genetic Testing in Persons with Multiple Colorectal Polyps, Clinical Gastroenterology and Hepatology (2019), doi: j.cgh This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Utility of Genetic Testing in Persons with Multiple Colorectal Polyps Word Count: 1322 Khalaf N, MD, MPH and Samadder NJ, MD, MS Baylor College of Medicine, Houston, TX and Mayo Clinic, Phoenix, AZ COI: The authors have no conflicts of interest to declare. Authors: Natalia Khalaf, MD, MPH Assistant Professor, Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX Address: 2002 Holcombe Blvd, Houston, TX Phone: Fax: Niloy Jewel Samadder, MD, MS Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Phoenix, AZ Address: 5777 E. Mayo Boulevard, Phoenix, AZ Phone: Fax:

3 Colorectal cancer (CRC) is the fourth most common cancer among men and women and the second leading cause of cancer-related mortality with an estimated 140,000 new cases diagnosed in 2018 and over 50,000 resultant deaths in the U.S. 1 Screening for CRC is widely believed to provide an opportunity to detect patients at high risk for developing CRC, remove precursor lesions or detect cancer at an earlier stage. 2 Genetic alterations play a role in the development of all CRCs. Adenomatous polyps are accepted as the precursor lesion for most CRC with a main driver mutation of the adenoma to carcinoma sequence being inactivation of the Adenomatous Polyposis Coli (APC) tumor suppressor gene found in 80-90% of all colon cancers. 3 6 Approximately 3-6% of all CRC cases are associated with highly penetrant hereditary gastrointestinal cancer syndromes, such as Lynch syndrome and other polyposis syndromes. Selection of patients for genetic testing is traditionally based on polyp burden (>10 tubular adenomas at a single colonoscopy or >20 tubular adenomas over a lifetime), polyp histology (hamartomatous or juvenile polyps), age at polyposis diagnosis, family history of cancer, presence of extra-intestinal cancers and other factors represented in clinical practice guidelines However, what remains unknown is how many inherited cancer predisposition syndromes would be detected by multigene panel testing (MGPT) if employed in all patients with an increased polyp burden irrespective of the often uncertain family history. In this issue of Clinical Gastroenterology and Hepatology, Stanich and colleagues describe the prevalence of polyposis- and CRC-associated inherited gene mutations in patients with multiple colon polyps ( 10). 11 In this cross-sectional study of 3,789 adult patients (age 18) with a history of 10 or more cumulative adenomatous or hamartomatous colorectal polyps who underwent MGPT at Ambry Genetics (Aliso Viejo, CA), the authors calculated the prevalence of pathogenic germline mutations overall and stratified by age, polyp type, and degree of polyposis. Persons with known familial mutations were excluded. The scope of gene testing varied among study participants (14-67 genes), however all had at least 14 polyposis and CRCassociated genes tested for (APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53). A subset of patients also underwent evaluation for three more newly discovered polyposis genes (GREM1, POLD1, and POLE), which were added to the Ambry Genetics MGPT assay during the course of the study period. The study analysis was limited to mutations found in the 17 major polyposis/crc genes listed above. 2

4 The majority of the patients (84.4%) had clinical adenomatous polyposis and only a minority (2%) had hamartomatous polyposis based on endoscopy results. A mutation in at least one gene on MGPT was found in 13.7% of tested persons (in all age groups and polyp cohorts). The prevalence of mutations ranged between 7.8% in patients with <20 polyps (any histology) and up to 47.8% in those with >100 polyps. The distribution of gene mutations in the study population was as follows: 138 mutations in non-polyposis CRC genes (MLH1, MSH2, MSH6, PMS2, EPCAM, TP53, CHEK2, CDH1); 286 mutations in adenomatous polyposis genes (APC, biallelic MUTYH, POLE, POLD1, constitutional mismatch repair deficiency); and 101 mutations in hamartomatous polyposis genes (SMAD4, BMPR1A, PTEN, STK11, GREM1). Currently, and as mentioned above, referral to a genetics specialist for consideration of MGPT for polyposis- or CRC-associated gene mutations is based on worrisome features such as >10 adenomas on a single colonoscopy, unusual polyp histology (hamartomatous polyps), or >10 adenomas plus concerning extracolonic manifestation or family history of cancer However, the results by Stanich et al. showed that nearly 14% of all patients with 10 or more adenomatous or hamartomatous polyps, irrespective of other clinical features or family history, had a genetic mutation identified in a CRC-predisposing gene on MPGT. Even in those with <20 cumulative adenomas (low polyp burden), 7.6% had a disease-associated genetic mutation, with 5.3% of these being in non-polyposis or hamartomatous cancer genes, which would not have been tested for if only genes specific for adenomatous polyposis syndromes were evaluated. Among the 1,324 patients with adenomas (42% of the adenoma polyp cohort), only 2.1% had mutations in APC or biallelic MUTYH genes and 0.2% in other adenomatous polyposis genes. Of interest, the most common mutations among this cohort (4.3%) were in non-polyposis colorectal cancer genes including 2.8% in Lynch syndrome genes. These findings highlight that testing for mutations limited to polyposis syndromes may miss other important CRCassociated mutations among persons with lower polyp burden (<20 adenomas) and raise the possibility of missed opportunities to diagnose several important syndromes (such as Lynch syndrome, Li Fraumeni syndrome, hereditary diffuse gastric cancer, CHEK2 breast-colon syndrome and several hamartomatous syndromes) with more restrictive genetic testing practices. Similar findings have been found in several studies using MGPT in an unselected cancer population including but not limited to CRC patients. Mandelkar et al. reported on 1,040 advanced cancer patients 3

5 (majority were stage 4) at a single academic institution undergoing MPGT with a 76 gene panel, that 17.5% had clinically actionable mutations conferring cancer susceptibility, 55% of which would not have been detected using current clinical guidelines. This further led to a discussion of change in therapy for 3.7% of patients. 12 More closely related to the current investigation, Yurgelun et al. found that amongst 1,058 unselected CRC patients who underwent MGPT (25 genes), nearly 10% had a pathogenic mutation, of which 31 patients (3%) had mutations in non-colorectal cancer genes. 13 The MGPT has become more affordable over the past decade. This, combined with the fact that the results have the potential to alter clinical management of patients and their relatives for colorectal and extra-colonic cancer screening, means more research is needed to risk stratify which patients are best served by MGPT. A major limitation of Stanich et al. s study is the referral bias inherent in data from a population derived from a testing laboratory. 11 Patients with hamartomatous polyps or tubular adenomas that are being referred and ultimately undergo genetic testing may not be representative of all patients with such pathology. The ability to generalize these findings to the wider population of patients undergoing screening and surveillance colonoscopies is limited due to this intrinsic bias in the study design. Furthermore, the data from prior studies on colon cancer-predisposing germline mutations are limited to persons already diagnosed with cancer, 12,13 which may be different than the findings in non-cancer (oligo-)polyposis patients. Only a study with a prospective design involving testing all patients with hamartomatous or tubular adenomas (with a specific polyp count cut off) will help answer the question of when and in whom to recommend MGPT more definitively. Adding to the complexity and limitations of MGPT in persons without a well-defined classic polyposis syndrome or hereditary CRC syndrome is the concern of finding and managing variants of unknown significance (VUS). In a review of hereditary CRC syndromes, it was estimated that up to 10% of Caucasians have VUS on genetic testing, 14 leading to uncertainty in diagnosing inherited syndromes and management strategies. This can lead to over screening (or under screening) and obvious anxiety for the patient and their families. Better identifying individuals and families who are likely to benefit from MGPT for hereditary polyposis and CRC syndromes is of immense value in terms of delivering high-quality, personalized healthcare and ultimately limiting cancer risk. We advocate for a wholistic approach to identifying and testing these patients, 4

6 first through risk assessment based on current recommendations to select patients with high adenoma burden (>10) or unusual polyp histology (hamartomatous or juvenile polyps), with special attention being paid to other high-risk characteristics such as young age (<50 years) at polyp onset, family history of cancer, known mutation in an affected relative, or personal history of an extra-colonic cancer. Consideration for more broad gene testing beyond APC and MUTYH to include non-polyposis related CRC genes is also likely important in polyposis patients as a means of identifying higher risk patients earlier, with the hope of decreasing cancer risk through more aggressive surveillance strategies. 5

7 References 1. Noone AM, Howlader N, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, , National Cancer Institute. Bethesda, MD, based on November 2017 SEER data submission, posted to the SEER web site, April Zauber AG, Winawer SJ, O Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 2012;366: Kinzler KW, Vogelstein B. Cancer-susceptibility genes. Gatekeepers and caretakers. Nature 1997;386:761, Goss KH, Groden J. Biology of the adenomatous polyposis coli tumor suppressor. J Clin Oncol Off J Am Soc Clin Oncol 2000;18: Segditsas S, Tomlinson I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 2006;25: Hadac JN, Leystra AA, Paul Olson TJ, et al. Colon Tumors with the Simultaneous Induction of Driver Mutations in APC, KRAS, and PIK3CA Still Progress through the Adenoma-to-carcinoma Sequence. Cancer Prev Res Phila Pa 2015;8: Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015;110: ; quiz Idos G, Gupta S. When Should Patients Undergo Genetic Testing for Hereditary Colon Cancer Syndromes? Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 2018;16: Gupta S, Provenzale D, Regenbogen SE, et al. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version J Natl Compr Cancer Netw JNCCN 2017;15: Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology 2006;130: Stanich PP, Pearlman R, Hinton A, et al. Prevalence of Germline Mutations in Polyposis and Colorectal Cancer-associated Genes in Patients With Multiple Colorectal Polyps. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc December Mandelker D, Zhang L, Kemel Y, et al. Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA 2017;318: Yurgelun MB, Kulke MH, Fuchs CS, et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol Off J Am Soc Clin Oncol 2017;35: Valle L. Genetic predisposition to colorectal cancer: where we stand and future perspectives. World J Gastroenterol 2014;20:

COLON CANCER & GENETICS VERMONT COLORECTAL CANCER SUMMIT NOVEMBER 15, 2014

COLON CANCER & GENETICS VERMONT COLORECTAL CANCER SUMMIT NOVEMBER 15, 2014 WENDY MCKINNON, MS, CGC CERTIFIED GENETIC COUNSELOR FAMILIAL CANCER PROGRAM UNIVERSIT Y OF VERMONT MEDICAL CENTER 1 CHARACTERISTICS