Research

JAMA Oncology | Original Investigation

Risk of Pancreatic Cancer Among Individuals

With Pathogenic Variants in the ATM Gene
Fang-Chi Hsu, MS; Nicholas J. Roberts, VetMB, PhD; Erica Childs, PhD; Nancy Porter, MS; Kari G. Rabe, MS;
Ayelet Borgida, MS; Chinedu Ukaegbu, BS; Michael G. Goggins, MD; Ralph H. Hruban, MD;
George Zogopoulos, MD; Sapna Syngal, MD; Steven Gallinger, MD; Gloria M. Petersen, PhD; Alison P. Klein, PhD

Supplemental content
IMPORTANCE Pathogenic germline variants in the ATM gene have been associated with
pancreatic cancer risk. Although genetic testing identifies these variants in approximately
1% to 3% of unselected patients with pancreatic cancer, the lifetime risk of pancreatic cancer
among individuals with pathogenic ATM variants has not been well estimated.

OBJECTIVE To estimate age-specific penetrance of pancreatic cancer in individuals with

a pathogenic variant in the ATM gene.

DESIGN, SETTING, AND PARTICIPANTS This was a multicenter cohort study of pancreatic cancer
family registries in the US and Canada using pedigree data from 130 pancreatic cancer
kindreds with a pathogenic germline ATM variant. Data analyses were performed from
January 2020 to February 2021.

MAIN OUTCOMES AND MEASURES Observational age-specific risk of pancreatic cancer.

Penetrance was estimated using modified segregation analysis.

RESULTS The study population of 130 families (123 [95%] White families) comprised 2227
family members (mean age [SD], 58 [22] years; 1096 [49%] women) with complete records
(ie, including familial relationships, pancreatic cancer diagnosis, ATM status, proband status,
and age), of which 155 individuals had positive results for an ATM pathogenic variant, 16 had
a negative result, and the remainder did not have a test result. In these 130 families, 217
individuals had pancreatic cancer: 78 families had 1 such member; 34 families had 2 such
members; and 18 families had 3 or more members with pancreatic cancer. The average
(range) age at diagnosis was 64 (31-98) years. The cumulative risk of pancreatic cancer
among individuals with a germline pathogenic ATM variant was estimated to be 1.1% (95% CI,
0.8%-1.3%) by age 50 years; 6.3% (95% CI, 3.9%-8.7%) by age 70 years; and 9.5% (95% CI,
5.0%-14.0%) by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95% CI,
4.5-9.5) in ATM variant carriers compared with noncarriers.

CONCLUSIONS AND RELEVANCE This multicenter cohort study found that individuals with
a germline pathogenic ATM variant were at an increased lifetime risk of pancreatic cancer.
These risk estimates can help guide decision-making when evaluating the risks and benefits
of enhanced early detection surveillance.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Alison P.
Klein, PhD, MHS, Department of
Oncology, Pathology, and Medicine,
Sidney Kimmel Comprehensive
Cancer Center, 1550 Orleans St,
JAMA Oncol. 2021;7(11):1664-1668. doi:10.1001/jamaoncol.2021.3701 Room 354, Baltimore, MD 21231
Published online September 16, 2021. (aklein1@jhmi.edu).

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 Risk of Pancreatic Cancer for ATM Variant Carriers Original Investigation Research

P
ancreatic ductal adenocarcinoma is among the most
lethal cancer types. In 2021, there will be an estimated Key Points
60 430 new pancreatic cancers diagnosed and 48 220
Objective To estimate the risk for pancreatic cancer among
related deaths in the US.1 Despite the near doubling of pan- individuals with a pathogenic variant in the ATM gene.
creatic cancer survival rates during the past decade, the 5-year
Findings This multicenter cohort study of 2227 members of 130
survival of approximately 10% remains the lowest of any
pancreatic cancer kindreds found that the risk of pancreatic cancer
major tumor type.1 Survival rates are higher for patients with
in individuals with a pathogenic variant in the ATM gene is 1.1% by
early-stage disease,1,2 highlighting the potential benefit of age 50 years, 6.3% by age 70 years, and 9.5% by age 80 years.
earlier detection.
Meaning The findings of this cohort study suggest that
Recently, germline genetic testing for patients with pan-
individuals with a pathogenic variant in the ATM gene are at a high
creatic cancer and their first-degree relatives has become the
risk of pancreatic cancer and may benefit from enhanced early
recommended standard of care3 because studies have dem- detection surveillance.
onstrated that pathogenic variants in the ATM, BRCA1, BRCA2,
CDKN2A, PALB2, PRSS1 STK11, TP53, and Lynch syndrome
jects (45 CFR §46). The study followed the Strengthening the
collectively occur in 4% to 10% of patients.4-7 While studies
Reporting of Observational Studies in Epidemiology (STROBE)
of the estimated risk of pancreatic cancer in carriers of a patho-
reporting guideline.
genic variant in these genes are limited, BRCA2 carriers are
estimated to have a 2- to 6-fold increased risk of developing
pancreatic cancer, BRCA1 carriers a 1- to 2.5-fold increased risk, Study Design and Participants
Included kindreds were enrolled in any of the family regis-
and CDKN2A carriers a higher 12-fold increased risk. Esti-
tries that participate in the Pancreatic Cancer Genetic Epide-
mated risk for these and other genes is presented in eTable 1
miology Consortium: the National Familial Pancreas Tumor
in the Supplement.6,8-11 Roberts and colleagues12 first re-
Registry (Johns Hopkins University); the Biospecimen Re-
ported the association between pathogenic ATM variants and
source for Pancreas Research (Mayo Clinic); GI Cancer Genet-
pancreatic cancer, observing pathogenic variants in 3% of pa-
ics (Dana-Farber Cancer Institute); and the Ontario Pancreas
tients with familial pancreatic cancer. Subsequent studies13
Cancer Study (Mount Sinai Hospital, University of Toronto).
have replicated these findings and demonstrated that as many
Registry eligibility required that families have a least 1 mem-
as 2.3% of patients with pancreatic cancer unselected for fam-
ber with pancreatic cancer. Families were eligible for inclu-
ily history harbor germline pathogenic ATM variants with an
sion if at least 1 family member was diagnosed with pancre-
odds ratio of 5.71 (95% CI, 4.38-7.33) in patients with pancre-
atic cancer and at least 1 individual in the pedigree had a
atic cancer compared with the control group of patients of
germline ATM pathogenic variant. Pathogenic ATM variants
European ancestry.6
were identified in these individuals either through clinical se-
The ATM gene product (OMIM 607585) is a serine/
quencing or previously published research-based sequenc-
threonine kinase that plays essential roles in DNA double-
ing studies.6,13,18,19 Information on familial relationships,
strand break repair, cell-cycle control, and apoptosis. Identi-
pancreatic cancer diagnosis, ATM status (pathogenic variant
fication of a germline ATM pathogenic variant in a patient with
carrier, noncarrier, or untyped), proband status, and age (at
pancreatic cancer may have implications for future treat-
diagnosis of pancreatic cancer or at last contact or death if not
ment decisions.14,15 Furthermore, carriers of an ATM patho-
diagnosed with pancreatic cancer) were obtained for pedi-
genic variant without cancer should consider the risks and ben-
gree members. Of the 130 families included in this study,
efits of cancer screening. The risk of breast cancer among
123 reported having European ancestry.
ATM pathogenic variant carriers has been determined to be
moderately elevated.16 However, the lifetime risk of pancre-
atic cancer in carriers has not been well defined. Individuals Statistical Analysis
Using the modified segregation analysis approach available in
with an inherited predisposition to pancreatic cancer, includ-
MENDEL, version 16.0,20 we estimated the cumulative risk of
ing those with a pathogenic ATM variant, may benefit from
pancreatic cancer by age dependent on germline ATM variant
surveillance.17 Better risk estimates can help guide decisions
status. In brief, using this approach, penetrance is estimated
regarding the role of pancreas surveillance in defined high-
by the maximum likelihood of the observed genetic data given
risk individuals. To this end, we sought to estimate age-
the phenotype of the observed pedigree members (age and
specific penetrance of pancreatic cancer in kindreds with
affection status). The genetic model includes the mode of in-
pathogenic ATM variants.
heritance, disease allele frequency, and penetrance function.
We assumed dominant inheritance and penetrance followed
a proportional hazards model where the age-specific pen-
Methods etrance (cumulative risk, F[t]) was calculated by
The study was reviewed and approved by the institutional re- cumulative incidence: Λ (t) = λ_0 (t) × e^ (β [t] gi),
view board of the Johns Hopkins Medical Institution. Written
informed consent was obtained by each recruiting registry and where gi is an indicator for ATM carrier status. A population
only deidentified data were provided for the study analyses pathogenic ATM variant frequency of 0.2% was assumed
according to the Regulations for the Protection of Human Sub- (between estimate of 0.35% and 0.1% in prior studies6,12) and

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 Research Original Investigation Risk of Pancreatic Cancer for ATM Variant Carriers

Table 1. Distribution of Age and Pancreatic Cancer Status Across the Study Population of 130 Families

ATM pathogenic variant status

Carriers Noncarriers Untyped
No. of
Age, y individuals PC No PC NA PC No PC NA PC No PC NA
Unknown 1214 0 0 0 0 0 0 2 517 695
0-29 273 0 3 0 0 2 0 0 257 11
30-39 180 0 3 1 0 6 0 2 153 15
40-49 274 8 13 0 2 1 0 11 206 33
50-59 348 31 8 1 0 1 0 25 236 46
60-69 458 41 13 2 0 3 0 28 336 35
70-79 411 19 2 1 1 0 0 25 337 26
80-89 323 6 2 0 0 0 0 12 289 14
≥90 150 1 0 0 0 0 0 3 141 5
Totala 3631 106 44 5 3 13 0 108 2472 880
Abbreviations: NA, not available; PC, pancreatic cancer. not otherwise contribute (eg, grandparents needed to establish that aunts
a
Those with missing data on age and/or pancreatic cancer status were included and uncles are siblings).
in the pedigree analysis because these individuals inform relationships but do

sensitivity analysis was conducted. The baseline cumulative
probability of pancreatic cancer was based on population cu-
mulative probabilities from the Surveillance, Epidemiology,
and End Results Program (US National Cancer Institute)21 for
2000 to 2017. Pedigree likelihoods were obtained using either
the Elston-Stewart22 or Lander-Green algorithms depending
on computational efficiency.23 To account for the selection of
families through a patient with pancreatic cancer and a known
pathogenic ATM variant, analysis was conditioned on either
a single proband (a patient with pancreatic cancer was ini-
tially found to have the ATM variant) or multiple probands
(a family member without pancreatic cancer with an ATM
pathogenic variant and their closest relative with pancreatic
cancer was untyped for ATM). Age to pancreatic cancer was
estimated using proportional hazards model, where the ATM
variant carrier status was the predictor. We tested the hypoth-
esis that penetrance was not dependent on ATM carrier sta-
tus. Individuals without pancreatic cancer were censored at
their age at last follow-up or age at death if deceased. Param-
eters were estimated using maximum-likelihood methods,
such that the penetrance estimates that maximized the pedi-
gree likelihoods were obtained, and variances were obtained
from the observed information matrix.
Statistical tests were 2-tailed and P values < .05 were con-
sidered statistically significant. Data analyses were per-
formed from January 2020 to February 2021 using MENDEL,
version 16.0,20 and R, version 4.0 (The R Foundation for
Statistical Computing).
Results
The study population of 130 families (123 [95%] White fami-
lies) comprised 2227 family members (mean age [SD], 58 [22]
years; 1096 [49%] women) with complete records (ie, includ-
ing familial relationships, pancreatic cancer diagnosis, ATM
status [pathogenic variant carrier, noncarrier, or untyped],
proband status, and age; Table 1). Of these, 155 individuals
had a test result that was positive for an ATM pathogenic
variant, 16 had a negative result, and the remaining individu-
als did not have a test result. Because of the small sample
size, race and ethnicity were categorized as White or non–
White according to family ancestry. A higher prevalence of
pancreatic cancer was observed in noncarriers compared
with untyped individuals, but this was because of preferen-
tial genetic testing of patients with cancer over cancer-free
individuals. Additional pedigree members with missing pan-
creatic cancer status and/or age were included to complete
the family structure, but this had a limited influence on the
risk estimates. In these 130 families, there were a total of 217
individuals with pancreatic cancer: 78 families with 1 family
member with pancreatic cancer, 34 families with 2 members,
and 18 families with 3 or more members. The average age
(range) at pancreatic cancer diagnosis was 64 (31-98) years.
Additional demographic information and pedigree details are
provided in eTable 2 in the Supplement.
The cumulative risk of pancreatic cancer in pathogenic
ATM variant carriers and noncarriers is shown in the Figure
and Table 2, and age and ATM variant status were associated
with pancreatic cancer risk. Cumulative risk of pancreatic can-
cer in ATM variant carriers increased from 0.08% (95% CI,
0.07%-0.09%) by age 30 years to 9.5% (95% CI, 5.0%-14.0%)
by age 80 years. To determine if there was evidence of pen-
etrance differences between men and women, we allowed
for sex-specific penetrance; however, it was not significant
in the study model (β = 0.12; SE, 0.11; P = .29). Sensitivity analy-
ses assuming a 10-fold increase and 5-fold decrease in ATM
pathogenic variant frequency demonstrated consistent esti-
mates of penetrance (data not shown).
Discussion
This study presents what is, to our knowledge, the first quan-
tification of the age-specific risk of pancreatic cancer. These
models, which included proband correction, demonstrated the

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 Risk of Pancreatic Cancer for ATM Variant Carriers Original Investigation Research

Figure. Cumulative Risk of Developing Pancreatic Cancer, Table 2. Risk of Pancreatic Cancer by ATM Pathogenic Variant Status
by ATM Pathogenic Variant Status and Age

Pancreatic cancer, % cumulative risk (95% CI)

20
Age, y ATM noncarrier ATM carrier
Cumulative risk of pancreatic cancer, y

Carrier 30 0.01 (0.002-0.02) 0.08 (0.07-0.09)

15 Noncarrier 40 0.05 (0-0.10) 0.30 (0.25-0.36)
SEER risk
50 0.17 (0-0.44) 1.08 (0.83-1.33)
60 0.47 (0-1.47) 3.03 (2.12-3.94)
10
70 0.99 (0-3.60) 6.28 (3.90-8.66)
80 1.53 (0-6.45) 9.53 (5.04-14.02)
5

Penetrance analysis in high-risk families typically yields

0
0 20 40
Age, y
The shaded area shows the 95% CIs and the dashed blue line denotes the risk
from 2000 to 2017 based on data from SEER, the Surveillance, Epidemiology,
and End Results Program (Surveillance Research Program, National Cancer
Institute; https://seer.cancer.gov/).
high lifetime risk of pancreatic cancer in ATM variant carri-
ers. The risk was estimated to be 6.3% by 70 years of age and
9.5% by 80 years, findings that inform the potential benefit of
early detection in these kindreds. Risk prior to age 50 years,
even in this high-risk population, remained low (approxi-
mately 1.0%), supporting the current consensus that pancre-
atic cancer screening should generally begin at age 50 years
among individuals with a germline pathogenic variant and
a family history of pancreatic cancer.17 While there is high
agreement that individuals with pathogenic variants in BRCA2
should be considered for early detection screening trials, there
is less agreement for inclusions of ATM variant carriers in
surveillance protocols because some previous studies6,11,24
have suggested that the risk of pancreatic cancer in ATM vari-
ant carriers is lower. The relative risk estimate of 6.5 (95% CI,
4.5-9.5) in ATM variant carriers is substantial. Compared with
studies that have estimated a 2.2- to 6.6-fold increased risk
of pancreatic cancer in BRCA2 variant carriers,6,11,24 the risk
estimates of the present study strongly support inclusion of
ATM variant carriers in screening trials.
higher-risk estimates when compared with alternative meth-
60 80 100 ods, even when proband corrections are implemented. How-
ever, this study’s risk estimate of an approximately 6.5-fold
(95% CI, 4.5-9.5) increased risk of pancreatic cancer is consis-
tent with estimates of prior studies6 that demonstrated a 5.7-
fold (95% CI, 4.4-7.3) increased prevalence of ATM patho-
genic variants in more than 3000 patients with pancreatic
cancer unselected for family history vs general population
controls.6 This concordance suggests that the present study’s
penetrance estimates are not greatly inflated because of in-
complete adjustment for ascertainment.
Limitations
The study population was predominantly of European ances-
try; thus, caution is needed when generalizing these results
to individuals of different ancestry. Future studies to better un-
derstand the risk of germline ATM variants in non–European
populations are needed and are underway.
Conclusions
This was multicenter cohort study found that the cumulative
risk of pancreatic cancer in ATM pathogenic variant carriers
was 9.5% by age 80 years. These findings underscore the need
to develop appropriate surveillance and intervention strate-
gies for these individuals at high-risk of developing pancre-
atic cancer.

ARTICLE INFORMATION
Accepted for Publication: June 18, 2021.
Published Online: September 16, 2021.
doi:10.1001/jamaoncol.2021.3701
Author Affiliations: Department of Oncology,
Sidney Kimmel Comprehensive Cancer Center,
Johns Hopkins University, Baltimore, Maryland
(Hsu, Roberts, Childs, Porter, Goggins, Hruban,
Klein); Department of Pathology, The Sol Goldman
Pancreatic Cancer Research Center, Johns Hopkins
University, Baltimore, Maryland (Roberts, Goggins,
Hruban, Petersen, Klein); Department of
Quantitative Health Sciences, Mayo Clinic,
Rochester, Minnesota (Rabe); Divison of General
Surgery, University of Toronto, Toronto, Ontario,
Canada (Borgida, Gallinger); Division of
Gastroenterology, Department of Medicine,
Johns Hopkins University, Baltimore, Maryland
(Ukaegbu, Goggins, Klein); The Research Institute
of the McGill University Health Centre and the
Rosalind and Morris Goodman Cancer Research
Centre of McGill University, Montreal, Quebec,
Canada (Zogopoulos); Population Sciences Division,
Dana-Farber Cancer Institute, Boston,
Massachusetts (Syngal); Gastroenterology Division,
Brigham and Women's Hospital, Boston,
Massachusetts (Syngal); Department of
Epidemiology, Johns Hopkins Bloomberg School
of Public Health, Baltimore, Maryland (Klein).
Author Contributions: Dr Klein had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: Hruban, Syngal, Petersen,
Klein.
Acquisition, analysis, or interpretation of data: Hsu,
Roberts, Childs, Porter, Rabe, Borgida, Ukaegbu,
Goggins, Zogopoulos, Syngal, Gallinger, Petersen,
Klein.
Drafting of the manuscript: Hsu, Klein.
Critical revision of the manuscript for important
intellectual content: Roberts, Childs, Porter, Rabe,
Borgida, Ukaegbu, Goggins, Hruban, Zogopoulos,
Syngal, Gallinger, Petersen, Klein.
Statistical analysis: Hsu, Childs, Rabe, Klein.
Obtained funding: Gallinger, Petersen, Klein.
Administrative, technical, or material support:
Porter, Ukaegbu, Goggins, Syngal, Gallinger,
Petersen, Klein.
Supervision: Zogopoulos, Syngal, Gallinger, Klein.
Conflict of Interest Disclosures: Dr Hruban
reported royalty distributions from a patent for
GNAS, the technology used in this study, which
is licensed under an agreement between Thrive
Earlier Detection (a subsidiary of Exact Sciences
Corporation) and Johns Hopkins University.

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 Research Original Investigation
Dr Syngal reported a patent for PREMM model
licensed to Myriad Genetics during the conduct of
the study. Dr Klein reported consulting fees from
Merck outside the submitted work. No other
disclosures were reported.
Funding/Support: This research was supported
by grants from the US National Cancer Institute:
P50CA62924 (Klein), P30CA006973 (Nelson),
R01CA132829 (Syngal), R00CA190889 (Roberts),
and R01CA097075 and P50CA102701 (Petersen);
the Bowen-Chapman Family Research Fund
(Syngal); Fonds de Recherche du Québec
(Zogopoulos); the Lustgarten Foundation;
the Rolfe Pancreatic Cancer Foundation
(Roberts and Petersen); the Sol Goldman
Pancreatic Cancer Research Center; and
the Troper Wojcicki Foundation.
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
REFERENCES
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer
statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33.
doi:10.3322/caac.21654
2. Blackford AL, Canto MI, Klein AP, Hruban RH,
Goggins M. Recent trends in the incidence and
survival of stage 1a pancreatic cancer:
a surveillance, epidemiology, and end results
analysis. J Natl Cancer Inst. 2020;112(11):1162-1169.
doi:10.1093/jnci/djaa004
3. Daly MB, Pilarski R, Yurgelun MB, et al.
NCCN Guidelines insights: genetic/familial high-risk
assessment: breast, ovarian, and pancreatic,
version 1.2020. J Natl Compr Canc Netw. 2020;18
(4):380-391. doi:10.6004/jnccn.2020.0017
4. Shindo K, Yu J, Suenaga M, et al. Deleterious
germline mutations in patients with apparently
sporadic pancreatic adenocarcinoma. J Clin Oncol.
2017;35(30):3382-3390. doi:10.1200/JCO.2017.72.
3502
5. Yurgelun MB, Chittenden AB,
Morales-Oyarvide V, et al. Germline cancer
1668 JAMA Oncology November 2021 Volume 7, Number 11 (Reprinted)
© 2021 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 05/18/2023
susceptibility gene variants, somatic second hits,
and survival outcomes in patients with resected
pancreatic cancer. Genet Med. 2019;21(1):213-223.
doi:10.1038/s41436-018-0009-5
6. Hu C, Hart SN, Polley EC, et al. Association
between inherited germline mutations in cancer
predisposition genes and risk of pancreatic cancer.
JAMA. 2018;319(23):2401-2409. doi:10.1001/jama.
2018.6228
7. Klein AP. Identifying people at a high risk of
developing pancreatic cancer. Nat Rev Cancer.
2013;13(1):66-74. doi:10.1038/nrc3420
8. Breast Cancer Linkage Consortium. Cancer risks
in BRCA2 mutation carriers. J Natl Cancer Inst.
1999;91(15):1310-1316. doi:10.1093/jnci/91.15.1310
9. Mocci E, Milne RL, Méndez-Villamil EY, et al. Risk
of pancreatic cancer in breast cancer families from
the breast cancer family registry. Cancer Epidemiol
Biomarkers Prev. 2013;22(5):803-811. doi:10.1158/
1055-9965.EPI-12-0195
10. Thompson D, Easton DF; Breast Cancer Linkage
Consortium. Cancer incidence in BRCA1 mutation
carriers. J Natl Cancer Inst. 2002;94(18):1358-1365.
doi:10.1093/jnci/94.18.1358
11. Thompson ED, Roberts NJ, Wood LD, et al.
The genetics of ductal adenocarcinoma of the
pancreas in the year 2020: dramatic progress, but
far to go. Mod Pathol. 2020;33(12):2544-2563.
doi:10.1038/s41379-020-0629-6
12. Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in
patients with hereditary pancreatic cancer. Cancer
Discov. 2012;2(1):41-46. doi:10.1158/2159-8290.CD-
11-0194
13. Roberts NJ, Norris AL, Petersen GM, et al.
Whole genome sequencing defines the genetic
heterogeneity of familial pancreatic cancer. Cancer
Discov. 2016;6(2):166-175. doi:10.1158/2159-
8290.CD-15-0402
14. Pitter KL, Casey DL, Lu YC, et al. Pathogenic
ATM mutations in cancer and a genetic basis for
radiotherapeutic efficacy. J Natl Cancer Inst. 2021;
113(3):266-273. doi:10.1093/jnci/djaa095
15. Lavin MF. Ataxia-telangiectasia: from a rare
disorder to a paradigm for cell signalling and cancer.
Risk of Pancreatic Cancer for ATM Variant Carriers
Nat Rev Mol Cell Biol. 2008;9(10):759-769.
doi:10.1038/nrm2514
16. Thompson D, Duedal S, Kirner J, et al.
Cancer risks and mortality in heterozygous ATM
mutation carriers. J Natl Cancer Inst. 2005;97(11):
813-822. doi:10.1093/jnci/dji141
17. Goggins M, Overbeek KA, Brand R, et al;
International Cancer of the Pancreas Screening
(CAPS) consortium. Management of patients
with increased risk for familial pancreatic cancer:
updated recommendations from the International
Cancer of the Pancreas Screening (CAPS)
Consortium. Gut. 2020;69(1):7-17. doi:10.1136/
gutjnl-2019-319352
18. Zhen DB, Rabe KG, Gallinger S, et al. BRCA1,
BRCA2, PALB2, and CDKN2A mutations in familial
pancreatic cancer: a PACGENE study. Genet Med.
2015;17(7):569-577. doi:10.1038/gim.2014.153
19. Grant RC, Selander I, Connor AA, et al.
Prevalence of germline mutations in cancer
predisposition genes in patients with pancreatic
cancer. Gastroenterology. 2015;148(3):556-564.
doi:10.1053/j.gastro.2014.11.042
20. Lange K, Papp JC, Sinsheimer JS, Sripracha R,
Zhou H, Sobel EM. Mendel: the Swiss army knife of
genetic analysis programs. Bioinformatics. 2013;
29(12):1568-1570. doi:10.1093/bioinformatics/btt187
21. National Cancer Institute. Surveillance,
Epidemiology, and End Results Program,
2000-2017. Accessed August 17, 2021. https://seer.
cancer.gov/
22. Elston RC, Stewart J. A general model for the
genetic analysis of pedigree data. Hum Hered. 1971;
21(6):523-542. doi:10.1159/000152448
23. Lander ES, Green P. Construction of multilocus
genetic linkage maps in humans. Proc Natl Acad Sci
U S A. 1987;84(8):2363-2367. doi:10.1073/pnas.84.
8.2363
24. Iqbal J, Ragone A, Lubinski J, et al; Hereditary
Breast Cancer Study Group. The incidence of
pancreatic cancer in BRCA1 and BRCA2 mutation
carriers. Br J Cancer. 2012;107(12):2005-2009.
doi:10.1038/bjc.2012.483
jamaoncology.com