Prevalence and Spectrum of Germline Cancer Susceptibility
Gene Mutations Among Patients With Early-Onset Colorectal
Cancer
Rachel Pearlman, MS, CGC,
The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The
Ohio State University Wexner Medical Center, Columbus
Wendy L. Frankel, MD,
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
Corresponding Author: Heather Hampel, MS, CGC, The Ohio State University Comprehensive Cancer Center, Department of
Internal Medicine, The Ohio State University Wexner Medical Center, 2012 Kenny Rd, Columbus, OH 43221
(Heather.Hampel@osumc.edu).
Author Contributions: Mss Pearlman and Hampel had full access to all of the data in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.
Concept and design
: Hampel, Pearlman, Goldberg, Paskett, Shields, Freudenheim, de la Chapelle.
Acquisition, analysis, or interpretation of data
: All authors.
Drafting of the manuscript
: Pearlman, Hampel.
Critical revision of the manuscript for important intellectual content
: All authors.
Statistical analysis
: Liyanarachchi, Pearlman.
Obtained funding
: Hampel, Goldberg, Paskett, Shields, Freudenheim, de la Chapelle.
Administrative, technical, or material support
: Frankel, Swanson, Zhao, Yilmaz, Miller, Bacher, Bigley, Nelsen, Allen, Pritchard,
Shirts, Jacobson.
Study supervision
: Hampel, Pearlman, Goldberg, Paskett, Shields, Freudenheim, de la Chapelle.
Conflict of Interest Disclosures: Myriad Genetics Inc donated the next-generation sequencing testing for mismatch repair–proficient
patients with CRC diagnosed younger than 50 years for this study. Dr Kalady discloses honorarium from Helomics and Transenterix
and is a member of the speakers’ bureau for Helomics. Ms Heald discloses a consulting or advising role with Invitae and Myriad
Genetics Inc and is a member of the speakers’ bureau for Myriad Genetics Inc. Dr Paquette has received honoraria from Medtronic
and has served on the speakers’ bureau. Dr Kuebler discloses employment with Columbus Oncology Associates, LLC. Dr Mahesh
discloses stock in Merck, Pfizer, Kite pharmaceuticals, Oncothyreon, and Exelixis. Ms Buie discloses research funding from Merck,
Galera, Amgen, and Celgene. Dr Haut discloses research funding from Amgen, Celgene, Incyte, Conversant Bio, Evidera, EMD
Serono, Vector Oncology, Bristol Myers, GlaxoSmithKline, Eli Lilly, Luitpold pharmaceuticals, and Sanofi pharmaceuticals. Mr Allen
discloses employment and stock with Myriad Genetics Inc. Dr de la Chapelle discloses a patent or intellectual property interest with
Genzyme and Ipsogen. Ms Hampel discloses a consulting or advising role with Invitae, research funding from Myriad Genetics Inc,
and honoraria from Beacon LBS. No other conflicts are reported.
Group Information: A full list of the OCCPI study group members can be found at https://cancer.osu.edu/research-and-education/
pelotonia-funded-research/statewide-colon-cancer-initiative/occpi-work-group.
Additional Contributions: The authors are grateful to the patients, families, and network of 51 hospitals across Ohio (eTable 1 in the
Supplement) who participated in the OCCPI study. In particular, the authors would like to thank the following hospitals for enrolling
at least 1 patient included in this study: Adena Regional Medical Center, Akron General Medical Center, Atrium Medical Center,
Aultman Hospital, Bethesda North Hospital-TriHealth, Blanchard Valley Health System, Cleveland Clinic Foundation, Doctors
Hospital, Fairfield Medical Center, Fairview Hospital, Genesis HealthCare System, Good Samaritan Hospital (Dayton), Good
Samaritan Hospital-TriHealth, Grady Memorial Hospital, Grant Medical Center, Hillcrest Hospital, Kettering Medical Center, Licking
Memorial Hospital, Marietta Memorial Hospital, Mercy Fairfield Hospital, Mercy Medical Center, MetroHealth Medical Center,
Miami Valley Hospital, Mount Carmel East Hospital, Mount Carmel St Ann’s, Mount Carmel West Hospital, ProMedica Flower
Hospital, Riverside Methodist Hospital, Springfield Regional Medical Center, St Luke’s Hospital, St Rita’s Medical Center, Summa
Akron City Hospital, The Christ Hospital, The Ohio State University, Upper Valley Medical Center, Wayne HealthCare, and Wright-
Patterson Medical Center. The authors also thank Ohio State University undergraduate student interns Angela Onorato, James Miner,
Jessica Purnell, Emily McDowell, Hannah Datz, Chloe Kent and Michael Bigley, who assisted with database entry and sample
processing. They received no compensation beyond their hourly payment as part-time Ohio State University Comprehensive Cancer
Center employees. The authors would also like to thank the National Cancer Institute Community Oncology Research Program and
the Dayton Clinical Oncology Program for their collaboration on this research study. They received reimbursement for their expenses
performing oversite for the study. Written permission was obtained for all persons named in the Additional Contribution section.
HHS Public Access
Author manuscript
JAMA Oncol
. Author manuscript; available in PMC 2018 April 01.
Published in final edited form as:
JAMA Oncol
. 2017 April 01; 3(4): 464–471. doi:10.1001/jamaoncol.2016.5194.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Benjamin Swanson, MD,
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
Weiqiang Zhao, MD, PhD,
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
Ahmet Yilmaz, PhD,
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
Kristin Miller, BS,
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
Jason Bacher, BA,
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
Christopher Bigley, MS,
The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The
Ohio State University Wexner Medical Center, Columbus
Lori Nelsen, BA,
The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The
Ohio State University Wexner Medical Center, Columbus
Paul J. Goodfellow, PhD,
The Ohio State University Comprehensive Cancer Center, Department of Obstetrics and
Gynecology, The Ohio State University Wexner Medical Center, Columbus
Richard M. Goldberg, MD,
The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The
Ohio State University Wexner Medical Center, Columbus
Electra Paskett, PhD,
The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The
Ohio State University Wexner Medical Center, Columbus
Peter G. Shields, MD,
The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The
Ohio State University Wexner Medical Center, Columbus
Jo L. Freudenheim, PhD,
Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York
Peter P Stanich, MD,
Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
Ilene Lattimer, BSN,
The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The
Ohio State University Wexner Medical Center, Columbus
Mark Arnold, MD,
Department of Surgery, The Ohio State University Wexner Medical Center, Columbus
Sandya Liyanarachchi, MS, MAS,
Pearlman et al.
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Author Manuscript Author Manuscript Author Manuscript Author Manuscript
The Ohio State University Comprehensive Cancer Center, Department of Cancer Biology and
Genetics, The Ohio State University Wexner Medical Center, Columbus
Matthew Kalady, MD,
Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio
Brandie Heald, MS, CGC,
Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio
Carla Greenwood, AA,
Department of Digestive Diseases and Surgery, Cleveland Clinic, Cleveland, Ohio
Ian Paquette, MD,
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
Marla Prues, RN,
Cancer Center Research, The Christ Hospital Health Network, Cincinnati, Ohio
David J. Draper, MD,
TriHealth Cancer Institute, Good Samaritan Hospital, Cincinnati, Ohio
Carolyn Lindeman, MSN,
TriHealth Cancer Institute, Good Samaritan Hospital, Cincinnati, Ohio
J. Philip Kuebler, MD, PhD,
Columbus Oncology and Hematology Associates, Columbus, Ohio
Kelly Reynolds, BS,
Department of Cancer Services, Riverside Methodist Hospital, Columbus, Ohio
Joanna M. Brell, MD,
Department of Medicine, MetroHealth Medical Center, Cleveland, Ohio
Amy A. Shaper, MSW,
Research Institute, MetroHealth Medical Center, Cleveland, Ohio
Sameer Mahesh, MD,
Department of Internal Medicine, Summa Cancer Institute, Summa Akron City Hospital, Akron,
Ohio
Nicole Buie, RN,
Summa Center for Clinical Trials, Summa Akron City Hospital, Akron, Ohio
Kisa Weeman, MD,
Department of Hematology/Oncology, Aultman Hospital, Canton, Ohio
Kristin Shine, BSN,
Department of Oncology Clinical Trials, Aultman Hospital, Canton, Ohio
Mitchell Haut, MD,
Mercy Medical Center, Canton, Ohio
Joan Edwards, RN,
Mercy Medical Center, Canton, Ohio
Pearlman et al.
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Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Shyamal Bastola, MD,
Department of Oncology and Hematology, Genesis HealthCare System, Zanesville, Ohio
Karen Wickham, RN,
Department of Oncology and Hematology, Genesis HealthCare System, Zanesville, Ohio
Karamjit S. Khanduja, MD,
Division of Colon and Rectal Surgery, Mount Carmel East Hospital, Columbus, Ohio
Rosemary Zacks, RN,
Department of Clinical Trials, Mount Carmel East Hospital, Columbus, Ohio
Colin C. Pritchard, MD, PhD,
Department of Laboratory Medicine, University of Washington, Seattle
Brian H. Shirts, MD, PhD,
Department of Laboratory Medicine, University of Washington, Seattle
Angela Jacobson, MS, CGC,
Department of Laboratory Medicine, University of Washington, Seattle
Brian Allen, MS, CGC,
Myriad Genetics Inc, Salt Lake City, Utah
Albert de la Chapelle, MD, PhD, and
The Ohio State University Comprehensive Cancer Center, Department of Cancer Biology and
Genetics, The Ohio State University Wexner Medical Center, Columbus
Heather Hampel, MS, CGC
The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The
Ohio State University Wexner Medical Center, Columbus
for the Ohio Colorectal Cancer Prevention Initiative Study Group
Abstract
IMPORTANCE—Hereditary cancer syndromes infer high cancer risks and require intensive
cancer surveillance, yet the prevalence and spectrum of these conditions among unselected
patients with early-onset colorectal cancer (CRC) is largely undetermined.
OBJECTIVE—To determine the frequency and spectrum of cancer susceptibility gene mutations
among patients with early-onset CRC.
DESIGN, SETTING, AND PARTICIPANTS—Overall, 450 patients diagnosed with colorectal
cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio
Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair
(MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry.
Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation
sequencing.
MAIN OUTCOMES AND MEASURES—Mutation prevalence and spectrum in patients with
early-onset CRC was determined. Clinical characteristics were assessed by mutation status.
Pearlman et al.
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RESULTS—In total 450 patients younger than 50 years were included in the study, and 75 gene
mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient
tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13,
MLH1
[including one with constitutional
MLH1
methylation]; 16,
MSH2;
1, MSH2/monoallelic
MUTYH;
2,
MSH6;
5,
PMS2
); 1 patient had the
APC
c.3920T>A, p.I1307K mutation and a
PMS2
variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline
biallelic
MUTYH
mutations); and 1 patient had somatic
MLH1
methylation. Four hundred two
patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9
had mutations in high-penetrance CRC genes (5,
APC;
1,
APC/PMS2;
2, biallelic
MUTYH;
1,
SMAD4
); 13 patients had mutations in high- or moderate-penetrance genes not traditionally
associated with CRC (3,
ATM
; 1,
ATM/CHEK2;
2,
BRCA1;
4,
BRCA2;
1,
CDKN2A;
2,
PALB2
);
10 patients had mutations in low-penetrance CRC genes (3,
APC
c.3920T>A, p.I1307K; 7,
monoallelic
MUTYH
). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not
meet established genetic testing criteria for the gene(s) in which they had a mutation.
CONCLUSIONS AND RELEVANCE—Of 450 patients with early-onset CRC, 72 (16%) had
gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and
testing with a multigene panel could be considered for all patients with early-onset CRC.
Colorectal cancer (CRC) is the third most common cancer diagnosed in the United States,
excluding nonmelanoma skin cancers.
1
The median age of CRC diagnosis is 69 years in
males and 73 years in females; 10% of patients with CRC are diagnosed when they are
younger than 50 years.
1
Early-onset cancer is a hallmark of inherited cancer predisposition.
Identification of hereditary cancer syndromes has significant implications for patients and
families, as it facilitates risk assessment, directs clinical management, and can guide
treatment options.
Lynch syndrome, caused by germline mutations in the mismatch repair (MMR) genes
MLH1, MSH2, MSH6
and
PMS2
, or
EPCAM
, is the most common known cause of
hereditary CRC and accounts for 4% to 13.5% of patients with early-onset CRC.
2–6
Patients
with tumors exhibiting characteristics of MMR deficiency are more likely to have Lynch
syndrome; therefore, professional guidelines recommend all patients with CRC receive
tumor screening for Lynch syndrome, with referral to genetic counseling for those with
MMR deficiency.
7,8
The National Comprehensive Cancer Network Clinical Practice
Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Colorectal (NCCN
Guidelines) suggests that all patients with CRC diagnosed younger than 50 years consider
genetic testing for Lynch syndrome.
9
The prevalence of other hereditary cancer syndromes among patients with early-onset CRC
is largely unknown because previous studies are limited and have been confined to selected
(high-risk) patient populations.
5,6
With the advent of next-generation sequencing (NGS),
genetic testing for hereditary CRC has shifted from phenotype-specific single gene
assessment to broad panels providing simultaneous assessment of multiple genes implicated
in various hereditary cancer syndromes. Previous studies have shown that multigene panel
testing for hereditary CRC is feasible, timely, and more cost-effective than single gene
Pearlman et al.
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