Risk of Non-Melanoma Cancers in First-Degree Relatives of CDKN2A Mutation Carriers

Article (PDF Available)inJournal of the National Cancer Institute 104(12):953-6 · April 2012with12 Reads
DOI: 10.1093/jnci/djs221 · Source: PubMed
Abstract
The purpose of this study was to quantify the risk of cancers other than melanoma among family members of CDKN2A mutation carriers using data from the Genes, Environment and Melanoma study. Relative risks (RRs) of all non-melanoma cancers among first-degree relatives (FDRs) of melanoma patients with CDKN2A mutations (n = 65) and FDRs of melanoma patients without mutations (n = 3537) were calculated as the ratio of estimated event rates (number of cancers/total person-years) in FDRs of carriers vs noncarriers with exact Clopper–Pearson-type tests and 95% confidence intervals (CIs). All statistical tests were two-sided. There were 56 (13.1%) non-melanoma cancers reported among 429 FDRs of mutation carriers and 2199 (9.4%) non-melanoma cancers in 23 452 FDRs of noncarriers. The FDRs of carriers had an increased risk of any cancer other than melanoma (56 cancers among 429 FDRs of carrier probands vs 2199 cancers among 23 452 FDRs of noncarrier probands; RR = 1.5, 95% CI = 1.2 to 2.0, P = .005), gastrointestinal cancer (20 cancers among 429 FDRs of carrier probands vs 506 cancers among 23 452 FDRs of noncarrier probands; RR = 2.4, 95% CI = 1.4 to 3.7, P = .001), and pancreatic cancer (five cancers among 429 FDRs of carrier probands vs 41 cancers among 23 452 FDRs of noncarrier probands; RR = 7.4, 95% CI = 2.3 to 18.7, P = .002). Wilms tumor was reported in two FDRs of carrier probands and three FDRs of noncarrier probands (RR = 40.4, 95% CI = 3.4 to 352.7, P = .005). The lifetime risk of any cancer other than melanoma among CDKN2A mutation carriers was estimated as 59.0% by age 85 years (95% CI = 39.0% to 75.4%) by the kin-cohort method, under the standard assumptions of Mendelian genetics on the genotype distribution of FDRs conditional on proband genotype.
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BRIEF COMMUNICATION
DOI: 10.1093/jnci/djs221 © The Author 2012. Published by Oxford University Press. All rights reserved.
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however, these associations are not well
established ( 2 , 3 , 6 , 9 , 11 13 ). The purpose of
this study was to estimate the relative risks
of non-melanoma cancers in family mem-
bers of CDKN2A mutation carriers. We
then estimated the lifetime risk for non-
melanoma cancers in CDKN2A carriers by
the kin-cohort method.
Probands for this study were recruited
for the Genes Environment and Melanoma
Study, a multicenter , international popu-
lation-based case control study. The
details of the Genes, Environment and
Melanoma study have been previously
published ( 17 ), and the lifetime risk of
melanoma among CDKN2A carriers has
been reported previously as well ( 18 , 19 ).
Probands were incident melanoma
patients with either fi rst or subsequent
melanoma who were identifi ed in nine
geographic regions in Australia, Canada,
the United States, and Italy.
We sought to estimate the relative
risks (RRs) for developing various can-
cers in family members of probands with
known CDKN2A mutations by comparing
the cancer incidence in rst-degree rela-
tives ( FDRs ) of carriers with cancer inci-
dence in FDRs of noncarriers. Relative
risks were calculated as the ratio of esti-
mated event rates (number of cancers/
total person-years) in FDRs of carriers
vs noncarriers. Exact Clopper Pearson-
type 95% confi dence intervals (CIs) for
the relative risks and the corresponding
Clopper Pearson-type exact binomial test
for ratios of two proportions with corre-
sponding two-sided P values were also cal-
culated. We then used the kin-cohort
design ( 20 23 ) to estimate cancer risks in
CDKN2A carriers. The kin-cohort method
uses the disease status data in relatives and
genotype data on the proband. The method
permits estimation of the risk in carriers as
a function of risks in relatives of carriers
and relatives of noncarriers and makes
standard Mendelian genetics assumptions
on the genotype distribution of unobserved
genotypes in FDRs conditional on the
observed genotype status of the proband.
Population-based sampling of probands
provides an important advantage over prior
study designs because it minimizes ascer-
tainment bias.
Germline CDKN2A mutations are associ-
ated with an increased risk of melanoma ( 1 )
and other cancers ( 2 14 ), although the risk
for cancers other than melanoma are less
well quantified. Germline CDKN2A is very
rare in the population with an estimated
prevalence of 0.01% ( 15 ). CDKN2A muta-
tions have been found in 1.2% of patients
with single primary melanoma, in 3.0% of
patients with multiple primary melanomas,
and in 10% 25% of multiple-case mela-
noma families ( 16 ).
Pancreatic cancer is one of the most
commonly reported non-melanoma can-
cers to be associated with germline
CDKN2A mutations ( 4 8 , 10 ). Germline
CDKN2A mutations have also been associ-
ated with an increased risk of other gastro-
intestinal cancers ( 4 , 8 ), even after excluding
pancreatic cancer ( 5 ). Several reports sug-
gest that CDKN2A mutations may also be
associated with an increased risk of breast
cancer, lung cancer, childhood cancers, and
squamous cancers of the head and neck;
Risk of Non-Melanoma Cancers in First-
Degree Relatives of CDKN2A Mutation
Carriers
Bhramar Mukherjee , John Oliver DeLancey , Leon Raskin , Jessica Everett ,
Joanne Jeter , Colin B. Begg , Irene Orlow , Marianne Berwick , Bruce
K. Armstrong , Anne Kricker , Loraine D. Marrett , Robert C. Millikan , Hoda
Anton Culver , Stefano Rosso , Roberto Zanetti , Peter A. Kanetsky , Lynn From ,
Stephen B. Gruber , for the GEM Study Investigators
Manuscript received September 23 , 2011 ; revised March 15 , 2012 ; accepted
March 16 , 2012
Correspondence to: Stephen B. Gruber, MD, PhD, MPH, University of Southern California Norris
Comprehensive Cancer Center, 1441 Eastlake Ave, NOR 8302L, Los Angeles, CA 90089-9181 (email:
sgruber@usc.edu ).
The purpose of this study was to quantify the risk of cancers other than melanoma
among family members of CDKN2A mutation carriers using data from the Genes,
Environment and Melanoma study. Relative risks (RRs) of all non-melanoma can-
cers among first-degree relatives (FDRs) of melanoma patients with CDKN2A muta-
tions (n = 65) and FDRs of melanoma patients without mutations (n = 3537) were
calculated as the ratio of estimated event rates (number of cancers/total person-
years) in FDRs of carriers vs noncarriers with exact Clopper Pearson-type tests and
95% confidence intervals (CIs). All statistical tests were two-sided. There were 56
(13.1%) non-melanoma cancers reported among 429 FDRs of mutation carriers and
2199 (9.4%) non-melanoma cancers in 23 452 FDRs of noncarriers. The FDRs of carriers
had an increased risk of any cancer other than melanoma (56 cancers among 429
FDRs of carrier probands vs 2199 cancers among 23 452 FDRs of noncarrier probands;
RR = 1.5, 95% CI = 1.2 to 2.0, P = .005), gastrointestinal cancer (20 cancers among 429
FDRs of carrier probands vs 506 cancers among 23 452 FDRs of noncarrier probands;
RR = 2.4, 95% CI = 1.4 to 3.7, P = .001), and pancreatic cancer (five cancers among 429
FDRs of carrier probands vs 41 cancers among 23 452 FDRs of noncarrier probands;
RR = 7.4, 95% CI = 2.3 to 18.7, P = .002). Wilms tumor was reported in two FDRs of
carrier probands and three FDRs of noncarrier probands (RR = 40.4, 95% CI = 3.4 to
352.7, P = .005). The lifetime risk of any cancer other than melanoma among CDKN2A
mutation carriers was estimated as 59.0% by age 85 years (95% CI = 39.0% to 75.4%)
by the kin-cohort method, under the standard assumptions of Mendelian genetics on
the genotype distribution of FDRs conditional on proband genotype.
J Natl Cancer Inst 2012;104: 1 4
953–956
© The Author 2012. Published by Oxford University Press. All rights reserved.
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To characterize the risk estimates , we
compared the reported history of cancer
among the set of 429 FDRs identifi ed by
the 65 probands who were determined to
be carriers with the reported history among
23 452 FDRs identifi ed by 3537 probands
who were not carriers. Total person-years
in FDRs of carriers were 20 298 years and
123 073 years for FDRs of noncarriers.
There were 56 (13.1%) non-melanoma
cancers reported among 429 FDRs of
mutation carriers and 2199 (9.4%) non-
melanoma cancers in 23 452 FDRs of non-
carriers. Overall rate ratios for cancer
incidence in FDRs of carriers was com-
pared with FDRs of noncarriers and corre-
sponding exact Clopper Pearson- type tests
and confi dence intervals were calculated
( http :// cran . r - project . org / web / packages / rater
atio . test / ). We used the marginal likelihood
CONTEXT AND CAVEATS
Prior knowledge
Germline CDKN2A mutations are associ-
ated with an increased risk of melanoma.
The relationship between CDKN2A muta-
tions and the risk for non-melanoma cancers
has not been well studied, in part , because
these mutations are rare in the general
population.
Study design
Data from family members of CDKN2A mu-
tation carriers were used to calculate the
relative and lifetime risks of non-melanoma
cancers.
Contribution
First-degree relatives of CDKN2A mutation
carriers had an increased risk for all non-
melanoma cancers, gastrointestinal cancer,
and colorectal cancer. These individuals also
had an increased lifetime risk of developing
any cancer, excluding melanoma, compared
with first-degree relatives of noncarriers.
Implication
The increased risk of developing non-mela-
noma cancers among family members of
CDKN2A mutation carriers may influence
cancer screening and prevention for these
individuals.
Limitation
The small number of cancers observed
among the study participants should be
considered when interpreting the findings.
From the Editors
Table 1 . Number of different cancers among first-degree relatives (FDRs) of CDKN2A carriers
(n = 65) and non-carriers (n = 3537) in the Genes, Environment and Melanoma Study *
Site No. of cancers RR (95% CI) P
All non-melanoma cancer
FDRs of carriers 56 1.5 (1.2 to 2.0) .003
FDRs of noncarriers 2199
All gastrointestinal cancer
FDRs of carriers 20 2.4 (1.4 to 3.7) <.001
FDRs of noncarriers 506
Colorectal cancer
FDRs of carriers 10 1.9 (0.9 to 3.4) .10
FDRs of noncarriers 328
Other sites §
Pancreas
FDRs of carriers 5 7.4 (2.3 to 18.7) .002
FDRs of noncarriers 41
Breast
FDRs of carriers 4 0.7 (0.2 to 1.8) .69
FDRs of noncarriers 339
Brain
FDRs of carriers 2 1.9 (0.2 to 7.1) .58
FDRs of noncarriers 64
Lung
FDRs of carriers 7 1.4 (0.6 to 3.0) .44
FDRs of noncarriers 293
Wilms tumor
FDRs of carriers 2 40.4 (3.4 to 352.7) .005
FDRs of noncarriers 3
* A total of 3602 probands were included in the study. There were 429 FDRs of carriers and 23 452 FDRs
of noncarriers included in the analysis. CI = confidence interval; RR = relative risk.
RRs were the ratio of estimated event rates (number of cancers/total person-years) in FDRs of carriers vs
noncarriers. Exact Clopper Pearson-type 95% CIs for the RRs were also calculated.
Two-sided P values were calculated by the Clopper Pearson-type exact tests for ratios of binomial proportions.
§ Not all sites are reported in the table.
approach proposed by Chatterjee and
Wacholder ( 23 ) to estimate the penetrance
of different cancers in CDKN2A carriers,
accompanied by a bootstrap confi dence
interval (we used R-package kin-cohort,
http :// cran . r - project . org / web / packages / kin .
cohort / ). All statistical tests were two-sided.
A P value of less than .05 was considered
statistically signifi cant.
Table 1 shows a summary of cancers in
FDRs by carrier and noncarrier status. The
results indicate that FDRs of carriers of
CDKN2A mutation were at an increased risk
for all non-melanoma cancers (56 cancers
among 429 FDRs of carrier probands vs 2199
cancers among 23 452 FDRs of non-carrier
probands, RR = 1.5, 95% CI = 1.2 to 2.0),
gastrointestinal cancer (20 cancers among
429 FDRs of carrier probands vs 506 cancers
among 23 452 FDRs of noncarrier probands,
RR = 2.4, 95% CI = 1.4 to 3.7), and colo-
rectal cancer (10 cancers among 429 FDRs
of carrier probands vs 328 cancers among
23 452 FDR of noncarrier probands, RR =
1.9, 95% CI = 0.9 to 3.4). However, only
the relative risks for all non-melanoma and
gastrointestinal cancers are statistically
signifi cant ( P = .003 and P < .001, respec-
tively). A sevenfold increased risk of pancre-
atic cancer in FDRs that was also statistically
signifi cant was also observed ( ve cancers
among 429 FDRs of carrier probands vs 41
cancers among 23 452 FDR of noncarrier
probands, RR = 7.4, 95% CI = 2.3 to 18.7,
P = .002). A statistically signifi cant increased
risk for Wilms tumor in FDRs of carriers
was observed ( P = .005), although only two
Wilms tumors were reported in FDRs of
CKDN2A carrier probands and three in
FDRs of noncarrier probands (RR = 40.4,
95% CI = 3.4 to 352.7). Because the
numbers are very small, these results should
be interpreted with caution.
Age-specifi c cumulative risks from the
kin-cohort analyses in CDKN2A carriers
are presented in Figure 1 . The risk differ-
ence in carriers and noncarriers is more
pronounced in late age, greater than age 75
years for most cancer types investigated.
The lifetime risk of any cancer other than
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55 60 65 70 75 80 85
0.0 0.2 0.4 0.6 0.8
All non−melanoma cancers
Age, y
Cummulative risk
Carriers
Noncarriers
55 60 65 70 75 80 85
0.0 0.2 0.4 0.6 0.8
All GI cancers
Age, y
Cummulative risk
Carriers
Noncarriers
55 60 65 70 75 80 85
0.0 0.2 0.4 0.6 0.8
All colorectal cancers
Age, y
Cummulative risk
Carriers
Noncarriers
Figure 1 . Age-specifi c cumulative risks for all non-melanoma cancers, all gastrointestinal (GI) cancers, and colorectal cancer in CDKN2A mutation
carriers as obtained by a kin-cohort analysis. The dashed line represents the 95% bootstrap confi dence interval.
melanoma among CDKN2A mutation car-
riers was estimated as 59.0% (95% CI =
39.0% to 75.4%) by age 85 years. Additional
descriptive statistics stratifi ed by site,
analyses including extended relatives, and
numerical results from the kin-cohort
method corresponding to Figure 1 are
given in Supplementary Tables 1 3 (available
online).
Our study supports the fi ndings of pre-
vious studies that have shown an increased
risk for cancers other than melanoma in
CDKN2A carriers and offer more precise
less biased estimates of risk. Previous
reports have noted an increased risk for
gastrointestinal cancers, particularly pan-
creatic cancer ( 8 ). Our study observed
comparable increased risks for these can-
cers with the advantage of population-
based sampling. Contrary to two published
reports of an increased risk of breast cancer
among CDKN2A mutation carriers, we
observed that no increased risk though the
sample sizes are limited ( 7 , 9 ). An unexpected
nding from our study was an increased
risk for Wilms tumor. This particular
nding has not been previously reported
and may warrant further investigation, espe-
cially in light of two recent studies that
reported an increased risk for development
of childhood cancers ( 11 , 13 ).
One recent study examined the risk of
cancer for sites other than melanoma in
p16-Leiden mutation carriers and found
statistically signifi cantly increased risks of
digestive, eye/brain, female genital, lip/
mouth/pharynx, pancreatic, respiratory,
and non-melanoma skin cancers in known
carriers ( 24 ). This study reported relative
risks of 4.2 (95% CI = 2.9 to 5.9) for can-
cers other than melanoma and 3.7 (95% CI
= 1.4 to 8.1) for digestive system cancers for
mutation carriers, results comparable to
those we obtained by the kin-cohort method.
Another recent kin-cohort study ( 25 )
reported penetrance of pancreatic cancer in
CDKN2A carriers by age 80 years to be
57.6% (95% CI = 7.8% to 85.6%) with a
relative risk estimate substantially higher
compared with that reported in our study.
The principal limitation of the Genes,
Environment and Melanoma study data is
that probands reports of cancer history in
relatives are prone to error without addi-
tional validation ( 26 , 27 ). This error, how-
ever, is likely to be non-differential because
the probands all had melanoma and did not
know their genotype at the time at which
they were asked about their family history
of cancer and is thus likely to lead to bias
toward the null in the risk estimates. The
comparatively small numbers of cancers in
CDNK2A mutation carriers’ families also
limit our fi ndings.
Any analysis of the impact of a single
gene relies on the assumption that if other
unknown genes infl uence risk, then their
effects are equivalent the two groups being
compared (eg, carriers vs noncarriers of the
gene under investigation). The infl uence of
other risk genes can result in extrafamilial
variation, and the marginal likelihood
method we used accounts for such residual
familial correlation after controlling for
CDKN2A status.
Our study provides further evidence
that CDKN2A mutations are associated
with increased risk for several cancers other
than melanoma. These results have impli-
cations for family members of CDKN2A
mutation carriers, even in the absence of
genetic testing, as they may infl uence
decisions and behaviors regarding screening
and preventative measures to be under-
taken or encouraged by physicians.
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Funding
The research was supported by grants from the
National Cancer Institute and National Institutes
of Health ( CA83180 to MB, CA98018 to MB
and SBG, CA046592 to SBG, CA014089 to SBG,
CA131010 to CBB, and CA156608 to BM).
Notes
The funders did not have a role in the study
design; data collection, analysis, or interpretation;
the writing of the brief communication; or the
decision to submit the brief communication for
publication.
Affiliations of authors: Department of
Biostatistics (BM), Department of Epidemiology
(SBG), Department of Internal Medicine (JODL,
LR, JE), and Department of Human Genetics,
University of Michigan, Ann Arbor, MI;
University of Arizona Comprehensive Cancer
Center, Tucson, AZ (JJ); Department of
Epidemiology and Biostatistics, Memorial
Sloan-Kettering Cancer Center New York, NY
(CBB, IO); Department of Epidemiology,
University of New Mexico, Albuquerque, NM
(MB); Sydney School of Public Health D02,
University of Sydney, Sydney, New South
Wales, Australia (BKA, AK); Department of
Epidemiology, Cancer Care Ontario, Toronto,
ON, Canada (LDM); Department of Epidemiology,
School of Public Health and Lineberger
Comprehensive Cancer Center, University of
North Carolina School of Medicine, Chapel
Hill, NC (RCM); Department of Epidemiology,
University of California Irvine, Irvine, CA
(HAC); Piedmont Cancer Registry, Centre for
Epidemiology and Prevention in Oncology in
Piedmont, Turin, Italy (SR, RZ); Department of
Epidemiology, University of Pennsylvania,
Philadelphia, PA (PAK); Department of
Dermatopathology, Women’s College
Hospital, Toronto, ON, Canada (LF), University
of Southern California Norris Comprehensive
Cancer Center, Los Angeles, CA (SBG) .
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    • "The cumulative incidence of breast cancer in different BRCA status groups of first-degree female relatives was estimated using Kaplan–Meier survival analyses. The breast cancer risk among female carriers of BRCA1 and BRCA2 mutations was estimated using the kin-cohort design [7, 12,[31][32][33][34][35][36][37][38]. All statistical tests were two-sided. "
    [Show abstract] [Hide abstract] ABSTRACT: BRCA1/2 mutations represent approximately 5 % of unselected Chinese women with breast cancer. However, the breast cancer risk of Chinese women with BRCA1/2 mutations is unknown. Therefore, the aim of this study was to estimate the age-specific cumulative risk of breast cancer in Chinese women who carry a BRCA1 or BRCA2 mutation. Our study included 1816 unselected Chinese women with breast cancer and 5549 female first-degree relatives of these probands. All probands were screened for BRCA1/2 mutation. The age-specific cumulative risks of BRCA1/2 carriers were estimated using the kin-cohort study by comparing the history of breast cancer in first-degree female relatives of BRCA1/2 carriers and non-carriers. Among the 1816 probands, 125 BRCA1/2 pathogenic mutations were identified (70 in the BRCA1 gene and 55 in the BRCA2 gene). The incidence of breast cancer in the first-degree female relatives of BRCA1/2 mutation carriers was significantly higher (3.7-fold and 4.4-fold for BRCA1 and BRCA2 mutation carriers, respectively) than in non-carriers. The estimated cumulative risks of breast cancer by age 70 years were 37.9 % [95 % confidence interval (CI) 24.1-54.4 %] for BRCA1 mutation carriers and 36.5 % (95 % CI 26.7-51.8 %) for BRCA2 mutation carriers, respectively. Our study suggests that the breast cancer risk of Chinese women with BRCA1/2 mutations appears to be relatively high by the age of 70. Therefore, genetic counseling, enhanced surveillance, and individual preventive strategies should be provided for Chinese women who carry a BRCA1/2 mutation.
    Full-text · Article · Mar 2016
  • [Show abstract] [Hide abstract] ABSTRACT: It is estimated that 5% to 10% of pancreatic cancer is familial. Although there is evidence of a major pancreatic cancer susceptibility gene, the majority of families with multiple cases of pancreatic cancer do not have an identifiable causative gene or syndrome. However, a subset of pancreatic cancer is attributable to known inherited cancer predisposition syndromes, including several hereditary breast cancer genes (BRCA1, BRCA2, and PALB2), CDKN2A, hereditary pancreatitis, hereditary nonpolyposis colorectal cancer, and Peutz-Jeghers syndrome. In addition to explaining a proportion of familial pancreatic cancer, individuals with these conditions are at increased risk for pancreatic cancer. Relatives from familial pancreatic cancer kindreds without one of these identifiable syndromes may have as high as a 32-fold risk of pancreatic cancer, depending on the number of affected first-degree relatives. Such high-risk individuals may benefit from increased surveillance, and strategies for early detection of pancreatic cancer are under evaluation.
    Article · Jul 2012
  • [Show abstract] [Hide abstract] ABSTRACT: A comprehensive family history is essential to identify patients at risk for hereditary cancer who could benefit from genetic counseling (GC). In a previous study, we observed a low occurrence of family history record (FHR) collection rate and GC referral among oncologists at our institution. The present work analyzes whether the implementation of a heredofamilial cancer unit (HFCU) would improve these parameters. We retrospectively compared the FHR rate in clinical records, National Cancer Institute (NCI) general criteria for hereditary cancer suspicion, GC referrals and FHR quality in two cohorts: cohort 1 (patients diagnosed before HFCU creation) and cohort 2 (after HFCU creation). Of 1,175 patients (590 cohort 1 and 585 cohort 2), FHRs were consigned in 27.3 % and 52.5 % of patients, respectively (p < 0.001). The GC referral of patients with any NCI criterion was 13.6 % xin cohort 1 vs. 40.5 % in cohort 2 (p < 0.001). FHR quality improved in terms of the total number of relatives (164 vs. 314, p = 0.1, N.S.) and number of healthy relatives consigned (80 vs. 191, p < 0.01). Nine mutations (6 BRCA, 1 MEN1, 2 Lynch), 4 unknown significance variants (all in BRCA) and 2 with no mutation were identified among patients referred from cohort 2. We conclude that the creation of a heredofamilial cancer unit has changed both FHR and GC referrals among oncologists at our institution, although continuous educational efforts are required.
    Article · Jun 2013
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