NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer.
Accreditation Statement
Physicians: National Comprehensive Cancer Network is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: National Comprehensive Cancer Network is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.
NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: 0836-0000-17-012-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the educational content; 2) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/81998; and 3) view/print certificate.
Release date: December 10, 2017; Expiration date: December 10, 2018
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Due to increased lifetime risks of multiple cancers associated with hereditary cancer syndromes, it is important to identify genes that may affect risk assessment and potential management strategies.1 In addition, early intervention has the potential to decrease cancer incidence and mortality in affected individuals.2,3 The recent introduction of multigene testing for hereditary forms of cancer has rapidly altered the clinical approach to testing at-risk patients and their families. Based on next-generation sequencing, multigene testing simultaneously analyzes a set of genes associated with a specific family cancer phenotype or multiple phenotypes, and may include syndrome-specific tests (ie, panels that test for only one syndrome, such as Lynch syndrome), cancer-specific tests (ie, panels that test for >1 gene associated with a specific type of cancer, such as colorectal cancer [CRC]), and comprehensive cancer panels (ie, panels that test for >1 gene associated with multiple cancers or cancer syndromes). The NCCN Guidelines
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
Multigene testing could include high-risk genes associated with a specific cancer or both high- and moderate-risk genes. Comprehensive cancer risk panels, which include a large number of genes associated with a variety of cancer types, are also available.4 The basis for using multigene testing for patient care should be no different from the rationale for testing a single gene known to be associated with the development of a specific type of cancer. Testing is ideally focused on identifying a mutation known to be clinically actionable. Specifically, a clinically actionable mutation alters patient management when present. Multigene testing may be most useful when more than one gene can explain a patient's clinical and family history. In these cases, multigene testing may be more efficient and/or cost-effective.4 Multigene testing may also be considered for those who tested negative for a particular syndrome but whose personal and family history is strongly suggestive of an inherited susceptibility.4,5
Multigene testing is associated with several challenges. Most multigene panels include genes with limited data regarding degree of cancer risk among carriers and that support guidelines for risk management.4,6–9 In addition, the cancer risk of many of these genes is not clear when ascertained in individuals who do not have the typical phenotype historically associated with the cancer gene.4 Further, it is possible that the risks associated with these genes may not be due entirely to that gene only, but may also be influenced by gene/gene or gene/environment interactions. Multigene tests also increase the likelihood of detecting variants of unknown/uncertain significance (VUS),4,5,8–12 with likelihood rates ranging from 17% to 38%.6,8,10,13 The considerable possibility of detecting a VUS adds to the complexity of counseling following multigene testing. Addressing these challenges will require large studies with adequate power to assess outcomes, yet such studies
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
There are other issues to consider regarding multigene testing. First, commercially available tests may differ significantly on a number of factors, such as number of genes analyzed, turnaround time, and insurance coverage. Tests requiring a longer turnaround time may not be suitable for patients who need rapid results to inform surgical decision-making or other treatment choices. In addition, there is variation across commercial laboratory providers in the interpretation of genetic variants or mutations; therefore, the specific laboratory and multigene test should be chosen carefully.4 Second, in some cases, next-generation sequencing may miss some mutations that would have been detected with traditional single-gene analysis.4 Third, mutations identified for more than one gene add complexity that may lead to difficulty in making risk management recommendations.5 A management plan should only be developed for identified gene mutations that are clinically actionable; care should be taken to ensure that overtreatment or overscreening does not occur due to findings for which clinical management is uncertain, or findings that are incorrectly interpreted due to lack of evidence. This issue is particularly salient when the clinical management under consideration may include prophylactic surgery, such as colectomy.
Multigene testing is a new and rapidly growing field, but there is currently a lack of evidence regarding proper procedures and risk management strategies that should follow testing, especially when mutations are found for moderate-risk genes or when a VUS is found. For this reason, the NCCN panel recommends multigene testing be offered in the context of professional genetic expertise, with pretest and posttest counseling. Panel recommendations are in agreement with those by ASCO, which issued an updated statement regarding genetic testing in 2015.14 Carriers of a genetic mutation should be encouraged to participate in clinical trials or genetic registries.
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017
Version 3.2017 © National Comprehensive Cancer Network, Inc. 2017, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 15, 12; 10.6004/jnccn.2017.0176
Multigene testing is not recommended when:
There is an individual from a family with a known mutation and there is no other reason for multigene testing;
The patient's family history is strongly suggestive of a specific known hereditary syndrome for which single-gene analysis may provide definitive diagnosis; or,
The patient is diagnosed with CRC with microsatellite instability (MSI) or loss of ≥1 DNA mismatch repair (MMR) proteins.
In these 3 scenarios, syndrome-specific panels may be considered.
Multigene testing may be considered in the following scenarios:
A patient with a personal or family history that meets criteria for >1 hereditary cancer syndrome (eg, Lynch syndrome and BRCA-related breast and/or ovarian cancer)
Colonic polyposis with uncertain histology
Adenomatous or mixed polyposis (specific to APC, MUTYH, POLE, and POLD1)
Family history does not meet criteria for established testing guidelines but there is suspicion of hereditary cancer, and an appropriate panel is available
Family history is limited or unknown but patient has concerns about hereditary cancer
As second-line testing when first-line testing (eg, syndrome-specific or single-gene) is inconclusive
However, additional indications for multigene testing may exist based on clinical judgment.
Risk for CRC and management of genes with well-established risk for CRC, including Lynch syndrome, familial adenomatous polyposis (FAP), and MUTYH-associated polyposis (MAP), have been reviewed in detail in prior NCCN Guidelines, and have been updated annually (to view the most recent and complete version of these guidelines, visit NCCN.org). In the case of many genes newly associated with CRC, the evidence is still emerging. To establish the clinical utility of these genes, it is important to review the strength of the evidence.15 Previously, the panel conditionally developed a framework of recommendations for genes commonly included in multigene panels (see GENE-7; page 1470). During the 2017 guidelines update meeting, the panel evaluated the strength of the evidence based on published reports supporting these genes. These NCCN Guidelines Insights summarize data focused on genes newly associated with CRC risk and current recommended management strategies, although the panel notes that the link between mutations/alterations in some of these genes and increased CRC risk is incompletely defined due to limited evidence. These include mutations/alterations in the following genes: APC (I1307K polymorphism), AXIN2, CHEK2, GREM1, MSH3, MUTYH (monoallelic), NTHL1, POLD1, and POLE.
Genes Newly Associated With CRC Frequently Seen on Multigene Panels: Evidence and Management Approaches
APC I1307K Mutation
The adenomatous polyposis coli (APC) gene is a tumor-suppressor gene associated with CRC.16 There is well-established evidence that the I1307K polymorphism in the APC gene, which occurs in approximately 6% to 8% of individuals of Ashkenazi Jewish decent, predisposes carriers to CRC.17–21 In an analysis of 3,305 individuals from Israel who underwent colonoscopic examinations, 8% were identified as carriers of the I1307K polymorphism, and the overall adjusted odds ratio (OR) for colorectal neoplasia among carriers was 1.51 (95% CI, 1.16–1.98).17 A subgroup analysis found that the prevalence of the I1307K polymorphism in individuals of Ashkenazi Jewish descent was 10.1% and the adjusted OR was 1.75 (95% CI, 1.26–2.45).17 A meta-analysis including 40 studies showed that compared with carriers of wild-type I1307K, individuals of Ashkenazi Jewish descent who carried the I1307K polymorphism had a significantly increased risk of colorectal neoplasia, with a pooled OR of 2.17 (95% CI, 1.64–2.86).20 Some studies have identified the I1307K polymorphism in the APC gene in individuals of non–Ashkenazi Jewish and Arabic descent, although the prevalence is higher in individuals of Ashkenazi Jewish descent.22–24 An analysis of 900 cases from a population-based case-control study in northern Israel found the I1307K polymorphism in the APC gene in 78 CRC cases, with a prevalence of 11.2%, 2.7%, and 3.1% among individuals of Ashkenazi Jewish, non-Ashkenazi Jewish, and Arabic descent, respectively.23 Overall, however, evidence is insufficient to determine whether risk for CRC associated with the APC I1307K polymorphism differs among individuals with Ashkenazi descent versus without, and the panel recognizes that some individuals may not be aware of their Ashkenazi heritage.
For carriers of the APC I1307K mutation with CRC, the panel recommends colonoscopy surveillance based on NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer and for Rectal Cancer (to view the most recent version of these guidelines, visit NCCN.org). For carriers of the APC I1307K mutation unaffected by CRC with a first-degree relative with CRC, the panel recommends colonoscopy surveillance every 5 years beginning at age 40 years or at 10 years younger than the first-degree relative's age at CRC diagnosis (see GENE-7; page 1470). For carriers unaffected by CRC without a first-degree relative with CRC, the panel recommends colonoscopy screening every 5 years beginning at age 40 years (see GENE-7; page 1470).
AXIN2 Mutations
Mutations in the Axin-related protein (AXIN2) gene are associated with polyposis and oligodontia.25–29 In a study of a 4-generation family from Finland, 11 family members had oligodontia, 8 of whom had either CRC or precancerous lesions, attributed to a nonsense mutation in the AXIN2 gene.25 Other studies also support the association of AXIN2 mutations and oligodontia.27,29 A report described a family with a history of oligodontia and other findings, including colonic polyposis, gastric polyps, a mild ectodermal dysplasia phenotype, and early-onset CRC and breast cancer, in which an inherited AXIN2 mutation (c.1989G>A) segregated in an autosomal dominant pattern.27 Another study of 23 families with FAP resulted in the identification of a novel AXIN2 variant (c.1387C>T) in one family with attenuated FAP (AFAP).28 Carriers of the variant had a variable number of polyps but no oligodontia or ectodermal dysplasia.28 During the 2017 update, AXIN2 was added to a list of genes commonly included on multigene panels (see GENE-4; page 1467). For carriers of AXIN2 mutations, the panel recommends initiation of colonoscopic surveillance at age 25 to 30 years, and if no polyps are located, a repeat colonoscopy every 2 to 3 years. If polyps are found, colonoscopic surveillance every 1 to 2 years is recommended, with consideration of surgical interventions if the polyp burden becomes unmanageable by colonoscopy (see GENE-7; page 1470).
CHEK2 Mutations
Germline mutations in the cell cycle checkpoint kinase 2 (CHEK2) gene are associated with increased risk of breast cancer and CRC.30–32 In a population-based study of 5,953 patients with breast, prostate, or colon cancers (1,934 patients with colon cancer), 533 were CHEK2-positive and 431 were affected relatives.30 After adjusting for mutation type, the risk of colon cancer was higher among relatives of probands with colon cancer than among relatives of patients with prostate or breast cancer (hazard ratio [HR], 4.2; 95% CI, 2.4–7.8; P=.0001).30 Significant associations between CHEK2 mutations and CRC risk have been identified in meta-analyses.31,32 One meta-analysis of 7 studies that included 4,029 cases and 13,844 controls based on search criteria found a significant association between the CHEK2 I157T variant and CRC risk.31 For carriers of CHEK2 mutations, the NCCN Panel recommends similar management strategies as described for carriers of the APC I1307K mutation.
GREM1 Alterations
Hereditary mixed polyposis syndrome (HMPS) is a rare autosomal dominant condition that occurs primarily in individuals of Ashkenazi Jewish descent and is characterized by multiple types of colorectal polyps, extracolonic tumors, onset of polyps in adolescence, and progression of some polyps to advanced adenomas.33,34 HMPS is due to a 40-kb duplication upstream of the gremlin 1 gene (GREM1), which increases ectopic GREM1 expression in normal epithelium.33 Exome sequencing combined with linkage analyses and detection of copy-number variations identified a 16-kb duplication upstream of GREM1 in a family of non–Ashkenazi Jewish descent with AFAP.35 For carriers of GREM1 alterations, the panel recommends similar management strategies as described for carriers of AXIN2 mutations (see GENE-7; page 1470).
MSH3 Mutations
MutS homolog 3 (MSH3) is a DNA MMR gene implicated in tumorigenesis of colon cancer with MSI.36 Recent data have suggested that biallelic MSH3 germline mutations are a recessive subtype of colorectal adenomatous polyposis.37 During the 2017 NCCN Guidelines update, MSH3 was added to a list of genes commonly included on multigene panels (see GENE-5; page 1468). However, given available data, the panel agreed that the strength of evidence linking MSH3 to increased CRC risk is not currently well established. For carriers of 2 MSH3 mutations, the panel recommends similar management strategies as described for carriers of AXIN2 mutations (see GENE-7; page 1470).
MUTYH (Monoallelic) Mutations
MUTYH is a base excision repair gene involved in repairing oxidative DNA damage. Individuals with a germline mutation in one allele of the MUTYH gene are thought to have a modest or slightly increased risk of CRC.38–40 A recent study suggests that the risks may be higher than previously estimated.41 This study analyzed 2,332 individuals with monoallelic MUTYH mutations among 9,504 relatives of 264 CRC cases with a MUTYH mutation. The estimated CRC risks, up to 70 years of age, were 7.2% for male carriers of monoallelic MUTYH mutations (95% CI, 4.6%–11.3%) and 5.6% for female carriers (95% CI, 3.6%–8.8%), irrespective of family history.41 The risks for CRC were higher for carriers of monoallelic MUTYH mutations with a first-degree relative with CRC.41 Another study evaluated the frequency of monoallelic MUTYH mutations and colorectal adenomas, and found that 13 of 72 individuals with CRC were monoallelic MUTYH mutation carriers, and 11 of the 13 had a family history of cancer in first- or second-degree relatives.42
During the 2017 update, the NCCN Panel revised management recommendations for monoallelic MUTYH mutation carriers based on the data and expert consensus (see GENE-7; page 1470). For probands unaffected by CRC with a first-degree relative with CRC, the panel recommends colonoscopy surveillance every 5 years, beginning at age 40 years or at 10 years younger than the age of the first-degree relative's age at CRC diagnosis. For probands unaffected by CRC without a first-degree relative with CRC, the panel notes that the data are not well established and it is uncertain whether specialized screening is warranted.
NTHL1 Mutations
The endonuclease III–like 1 (NTHL1) gene is involved in base excision repair and acts on oxidized pyrimidine residues.43 A recent study suggests a role for NTHL1 mutations in colorectal polyposis.44 Whole-exome sequencing on 51 individuals from 48 families diagnosed with polyposis identified a homozygous germline nonsense mutation in NTHL1 in 7 affected individuals from 3 unrelated families.44 During the 2017 update, NTHL1 was added to a list of genes commonly included on multigene panels (see GENE-6; page 1469). For carriers of 2 NTHL1 mutations, the panel recommends similar management strategies as described for carriers of AXIN2 mutations (see GENE-7; page 1470).
POLD1 and POLE Mutations
DNA polymerases delta [δ]1 (POLD1) and epsilon [ε] (POLE) are involved in DNA proofreading and replication.45 Mutations in the POLD1 and POLE genes may be associated with polyposis and an increased risk for CRC.46–49 Using whole-genome sequencing in combination with linkage and association analysis, heterozygous POLD1 and POLE germline variants were identified in multiple adenoma and/or CRC cases.47 In an analysis of 858 Spanish patients with early-onset and/or familial CRC and/or colonic polyposis, only 1 patient was found to have a POLE mutation.48 In an analysis of 266 unrelated probands with polyposis or who met the Amsterdam criteria, a POLE mutation was found in 1.5% of patients.50 Novel variants for both POLD1 and POLE have been identified in individuals with CRC, broadening the phenotypic spectrum of POLD1- and POLE-associated polyposis.46,51 Presently, for carriers of POLD1 and POLE mutations, the panel recommends similar management strategies as described for carriers of AXIN2 mutations (see GENE-7; page 1470).
Summary and Conclusions
During the panel meeting for the 2017 update, panel members discussed a number of important updates to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, including the strength of evidence linking mutations in genes newly associated with CRC risk and management recommendations for these genes. These include mutations/alterations in APC (I1307K polymorphism), AXIN2, CHEK2, GREM1 (upstream duplications), MSH3, MUTYH (monoallelic), NTHL1, POLD1, and POLE. Although research has demonstrated a potential risk for CRC associated with mutations in these genes, the value of including these genes for clinical testing (eg, as part of a multigene panel) remains uncertain. The panel urges caution in implementing routine clinical testing for genes for which the cancer risk and management strategies are currently uncertain, and some panel members have concerns about the observed practice of genetic testing companies regularly expanding the list of tested genes despite availability of only weak evidence to support cancer risk. Nonetheless, the panel recognizes that many testing companies offer panels that include these genes, and that patients are being tested and may need guidance regarding subsequent screening and surveillance. As additional data regarding the clinical significance of genes associated with CRC risk emerge, the NCCN Panel expects that these surveillance recommendations will continue to evolve.
References
- 1.↑
Yurgelun MB. Next-generation strategies for hereditary colorectal cancer risk assessment. J Clin Oncol 2015;33:388–393.
- 2.↑
Jarvinen HJ, Aarnio M, Mustonen H et al.. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000;118:829–834.
- 3.↑
Jarvinen HJ, Renkonen-Sinisalo L, Aktan-Collan K et al.. Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members. J Clin Oncol 2009;27:4793–4797.
- 4.↑
Hall MJ, Forman AD, Pilarski R et al.. Gene panel testing for inherited cancer risk. J Natl Compr Canc Netw 2014;12:1339–1346.
- 5.↑
Walsh T, Lee MK, Casadei S et al.. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A 2010;107:12629–12633.
- 6.↑
Cragun D, Radford C, Dolinsky JS et al.. Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clin Genet 2014;86:510–520.
- 7.
LaDuca H, Stuenkel AJ, Dolinsky JS et al.. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med 2014;16:830–837.
- 8.↑
Mauer CB, Pirzadeh-Miller SM, Robinson LD, Euhus DM. The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience. Genet Med 2014;16:407–412.
- 9.↑
Rainville IR, Rana HQ. Next-generation sequencing for inherited breast cancer risk: counseling through the complexity. Curr Oncol Rep 2014;16:371.
- 10.↑
Kapoor NS, Curcio LD, Blakemore CA et al.. Multigene panel testing detects equal rates of pathogenic BRCA1/2 mutations and has a higher diagnostic yield compared to limited BRCA1/2 analysis alone in patients at risk for hereditary breast cancer. Ann Surg Oncol 2015;22:3282–3288.
- 11.
Kurian AW, Hare EE, Mills MA et al.. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014;32:2001–2009.
- 12.↑
Tung N, Battelli C, Allen B et al.. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 2015;121:25–33.
- 13.↑
Yurgelun MB, Allen B, Kaldate RR et al.. Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology 2015;149:604–613.e620.
- 14.↑
Robson ME, Bradbury AR, Arun B et al.. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 2015;33:3660–3667.
- 15.↑
Easton DF, Pharoah PD, Antoniou AC et al.. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 2015;372:2243–2257.
- 16.↑
Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 2009;361:2449–2460.
- 17.↑
Boursi B, Sella T, Liberman E et al.. The APC p.I1307K polymorphism is a significant risk factor for CRC in average risk Ashkenazi Jews. Eur J Cancer 2013;49:3680–3685.
- 18.
Gryfe R, Di Nicola N, Lal G et al.. Inherited colorectal polyposis and cancer risk of the APC I1307K polymorphism. Am J Hum Genet 1999;64:378–384.
- 19.
Laken SJ, Petersen GM, Gruber SB et al.. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 1997;17:79–83.
- 20.↑
Liang J, Lin C, Hu F et al.. APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Am J Epidemiol 2013;177:1169–1179.
- 21.↑
Locker GY, Kaul K, Weinberg DS et al.. The I1307K APC polymorphism in Ashkenazi Jews with colorectal cancer: clinical and pathologic features. Cancer Genet Cytogenet 2006;169:33–38.
- 22.↑
Patael Y, Figer A, Gershoni-Baruch R et al.. Common origin of the I1307K APC polymorphism in Ashkenazi and non-Ashkenazi Jews. Eur J Hum Genet 1999;7:555–559.
- 23.↑
Rennert G, Almog R, Tomsho LP et al.. Colorectal polyps in carriers of the APC I1307K polymorphism. Dis Colon Rectum 2005;48:2317–2321.
- 24.↑
Shtoyerman-Chen R, Friedman E, Figer A et al.. The I1307K APC polymorphism: prevalence in non-Ashkenazi Jews and evidence for a founder effect. Genet Test 2001;5:141–146.
- 25.↑
Lammi L, Arte S, Somer M et al.. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet 2004;74:1043–1050.
- 26.
Lejeune S, Guillemot F, Triboulet JP et al.. Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis. Hum Mutat 2006;27:1064.
- 27.↑
Marvin ML, Mazzoni SM, Herron CM et al.. AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome. Am J Med Genet A 2011;155A:898–902.
- 28.↑
Rivera B, Perea J, Sanchez E et al.. A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia. Eur J Hum Genet 2014;22:423–426.
- 29.↑
Wong S, Liu H, Bai B et al.. Novel missense mutations in the AXIN2 gene associated with non-syndromic oligodontia. Arch Oral Biol 2014;59:349–353.
- 30.↑
Gronwald J, Cybulski C, Piesiak W et al.. Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband. Br J Cancer 2009;100:1508–1512.
- 31.↑
Liu C, Wang QS, Wang YJ. The CHEK2 I157T variant and colorectal cancer susceptibility: a systematic review and meta-analysis. Asian Pac J Cancer Prev 2012;13:2051–2055.
- 32.↑
Xiang HP, Geng XP, Ge WW, Li H. Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. Eur J Cancer 2011;47:2546–2551.
- 33.↑
Jaeger E, Leedham S, Lewis A et al.. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet 2012;44:699–703.
- 34.↑
Lieberman S, Walsh T, Schechter M et al.. Features of patients with hereditary mixed polyposis syndrome caused by duplication of GREM1 and implications for screening and surveillance. Gastroenterology 2017;152:1876–1880.e1.
- 35.↑
Rohlin A, Eiengard F, Lundstam U et al.. GREM1 and POLE variants in hereditary colorectal cancer syndromes. Genes Chromosomes Cancer 2016;55:95–106.
- 36.↑
Ikeda M, Orimo H, Moriyama H et al.. Close correlation between mutations of E2F4 and hMSH3 genes in colorectal cancers with microsatellite instability. Cancer Res 1998;58:594–598.
- 37.↑
Adam R, Spier I, Zhao B et al.. Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis. Am J Hum Genet 2016;99:337–351.
- 38.↑
Theodoratou E, Campbell H, Tenesa A et al.. A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br J Cancer 2010;103:1875–1884.
- 39.
Win AK, Cleary SP, Dowty JG et al.. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int J Cancer 2011;129:2256–2262.
- 40.↑
Win AK, Hopper JL, Jenkins MA. Association between monoallelic MUTYH mutation and colorectal cancer risk: a meta-regression analysis. Fam Cancer 2011;10:1–9.
- 41.↑
Win AK, Dowty JG, Cleary SP et al.. Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology 2014;146:1208–1211.e1–5.
- 42.↑
Rosner G, Bercovich D, Daniel YE et al.. Increased risk for colorectal adenomas and cancer in mono-allelic MUTYH mutation carriers: results from a cohort of North-African Jews. Fam Cancer 2015;14:427–436.
- 44.↑
Weren RD, Ligtenberg MJ, Kets CM et al.. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet 2015;47:668–671.
- 45.↑
Garg P, Burgers PM. DNA polymerases that propagate the eukaryotic DNA replication fork. Crit Rev Biochem Mol Biol 2005;40:115–128.
- 46.↑
Bellido F, Pineda M, Aiza G et al.. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet Med 2016;18:325–332.
- 47.↑
Palles C, Cazier JB, Howarth KM et al.. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 2013;45:136–144.
- 48.↑
Valle L, Hernandez-Illan E, Bellido F et al.. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Genet 2014;23:3506–3512.
- 49.↑
Elsayed FA, Kets CM, Ruano D et al.. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur J Hum Genet 2015;23:1080–1084.
- 50.↑
Spier I, Holzapfel S, Altmuller J et al.. Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas. Int J Cancer 2015;137:320–331.
- 51.↑
Esteban-Jurado C, Gimenez-Zaragoza D, Munoz J et al.. POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer. Oncotarget 2017;8:26732–26743.
