Annual Meeting Proceedings Part 1 - American Society of Clinical ...

1512 Poster Discussion Session (Board #1), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Routine universal screening for Lynch syndrome in colorectal cancer
patients in the community setting. Presenting Author: Jeffrey M. Goldberg,
Norton Cancer Institute, Louisville, KY
Background: Identification of colorectal cancer (CRC) cases that are due to
Lynch Syndrome (LS) is important to prevent secondary malignancies or
development of additional malignancies among relatives. Utilization of
clinical criteria to select CRC patients for laboratory testing fails to identify
a significant proportion of patients whose CRC is due to LS. Therefore,
universal screening for LS among CRC patients has been advocated by the
Evaluation of Genomic Applications in Practice and Prevention Working
Group. However, the feasibility of routine universal screening has not been
evaluated in a community-based, non-research setting. We implemented a
universal screening protocol for LS as part of routine care of CRC at Norton
Healthcare, a multi-institutional community-based healthcare organization.
Methods: Beginning in October 2009, all resected CRC tumors
automatically underwent immunohistochemistry analysis (IHC) for Lynch
Syndrome-associated mismatch repair gene (MMR) expression. Selected
patients who underexpressed MLH1 also underwent testing for the BRAF
V600E mutation. Patients who had a BRAF V600E mutation were considered
to have sporadic CRC. All other patients with abnormal IHC were
automatically referred for genetic counseling. We retrospectively reviewed
the outcomes of genetic counseling in all patients referred through this
universal screening protocol. Results: Between October 2009 and December
2011, 388 patients underwent resection of CRC, all of whom had IHC
for MMR expression. Seventy patients were identified as having abnormal
IHC. Sixty-two had MLH1/PMS2 underexpression, of which 18 underwent
BRAF testing and 13 had a BRAF V600E mutation. Eight had MSH2/MSH6
underexpression. Nine patients have been confirmed to have LS, 31 have
been found not to have LS, and 19 are in the process of evaluation. Seven
patients declined genetic counseling, and 4 died before they could be
adequately evaluated. Conclusions: Universal screening for CRC due to LS,
using IHC with select BRAF V600E mutation testing and automated
referral for genetic counseling, is feasible in the community setting.
Funded in part with federal funds: NCI, NIH, Contract No.
HHSN261200800001.
1514 Poster Discussion Session (Board #3), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Use of clinical history (CH) for Lynch syndrome (LS) risk assessment: An
economic decision analysis. Presenting Author: Sarmad Sadeghi, Cleveland
Clinic Taussig Cancer Institute, Cleveland, OH
Background: Previous studies comparing screening strategies (STs) for LS
concluded that immunohistochemistry (IHC)-based STs are most cost effective.
However, these analyses generally exclude clinical history (CH)-based criteria
due to concerns for reliability, e.g. Amsterdam (Ams), Bethesda (Beth), MMRpro
(Mpro), MMRpredict (Mpre) and PREMM (PRE). We conducted a comprehensive
comparison of all STs. Methods: Using assumptions from published reports we
performed a cost effectiveness analysis (CEA) with a societal viewpoint using
TreeAge software. 20 STs for proband (Pd) and general population (GP)
screening in a cohort of 100,000 assumed a 3% LS prevalence (Prev) in Pd and
0.23% in GP, 5 first degree relatives (FDRs) per LS diagnosis (Dx), 50% LS Prev
in FDRs, and 90% genetic testing (GT) compliance in Pds and GP and 52% in
FDRs. We used the number of LS Dxs as effectiveness measure (EM). Sensitivity,
accuracy, and incremental cost effectiveness ratios (ICERs) were calculated.
Results: The ST of Mpro followed by GT is highly sensitive and has an accuracy of
.997. Assuming 1-1.4 life years saved per Dx based on prior studies, this
strategy is also cost effective. Strategies with greater sensitivity were dominated
or not cost effective. Table shows results in order of increasing cost per Dx.
Conclusions: This comprehensive comparison suggests that Mpro is an appropriate
first step in screening for LS in Pds, and its routine use may be considered as
a quality measure in the management of colorectal cancer. IHC � BRAF, GT
should be reserved for Pds where CH is incomplete.
ST Sensitivity LS in Pds LS in FDRs ICER
No screening 0 0 0 -
Ams, IHC, GT .17 493 641 -
Ams, GT .2 594 772 -
Mpre, IHC, GT .55 1,546 2,010 -
Mpro, IHC, GT .72 1,994 2,593 $4.9K
Beth, IHC, GT .66 1,838 2,389 -
Mpre, GT .67 1,863 2,422 -
PRE, IHC, GT .73 2,017 2,622 -
Mpro, GT .88 2,403 3,124 $21.6K
Beth, GT .8 2,214 2,878 -
PRE, GT .89 2,430 3,159 $513K
IHC � BRAF, GT .82 2,241 2,913 -
IHC, GT .82 2,241 2,913 -
MSI, GT .84 2,295 2,983 -
PRE GP 4, GT age > 35 .89 110 144 -
PRE GP 3, GT age > 30 .89 120 156 -
PRE GP 2, GT age > 25 .89 129 168 -
PRE GP 1, GT age > 20 .89 138 179 -
MSI � IHC, GT .89 2,430 3,159 -
MSI � IHC � BRAF, GT .89 2,430 3,159 -
Up-front GT
- � dominated.
1 2,700 3,510 $1,053K
Cancer Prevention/Epidemiology
89s
1513 Poster Discussion Session (Board #2), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
An alternative approach to identify women at risk for colorectal cancer.
Presenting Author: Amanda S. Bruegl, University of Texas M. D. Anderson
Cancer Center, Houston, TX
Background: Hereditary colorectal cancer (CRC) is preventable; however,
identification of individuals at sufficiently high risk to warrant heightened
surveillance is difficult. Lynch Syndrome (LS) is an inherited cancer
syndrome due to germline mutation in a DNA mismatch repair gene. For
women with LS, the lifetime risk of endometrial cancer (EC) is 64% and
CRC is 54%. Fifty percent of women with LS will present with EC or ovarian
cancer prior to CRC. Therefore, women with LS associated EC represent an
ideal group for CRC prevention. The optimal method to identify women with
LS associated EC is not known. The purpose of this study was to determine
the utility of Amsterdam II and Society of Gynecologic Oncology (SGO)
Criteria (modified Bethesda criteria that use EC as the sentinel cancer) in
identifying women with LS associated EC. Our ultimate goal is to identify
women at increased risk of CRC. Methods: Immunohistochemistry (IHC) for
DNA mismatch repair proteins and MLH1 methylation analyses were used
to identify LS associated EC among 388 women. EC was designated as LS
if there was loss of mismatch repair protein expression. Absence of MLH1
methylation was required to confirm LS in tumors with MLH1 protein loss.
Results: Fifty-nine (15.2%) of the EC patients tested had LS. These
patients are summarized in the table. Conclusions: Clinical criteria to detect
LS identify 17/59 (29%) - 44/59 (74%) of women who present with EC
first. EC with MSH2 loss is most likely to occur in younger women and
women with positive family history of EC and CRC, features classically
associated with LS. In general, the MSH6 mutation is associated with older
age at diagnosis and fewer familial CRCs, however, we found a large
number of MLH1 (50%) and PMS2 (86%) cases diagnosed at greater than
50 years with no family history of CRC. Our data suggest that classic
clinical screening criteria are inadequate to detect patients with LS who
present with EC, potentially missing up to 25% of these patients.
Gene MLH1 MSH2 MSH6 PMS2 Total
Total number 14 27 11 7 59
Median age at diagnosis (range) 52 44 56 66 50
(42-79) (33-81) (31-76) (45-87) (31-87)
Diagnosis at greater than 50 years 7 8 9 6 30
FH CRC 3 16 4 3 26
Amsterdam criteria 3 13 0 1 17
SGO criteria 11 22 7 4 44
1515 Poster Discussion Session (Board #4), Sun, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Next-generation sequencing to identify candidate gene for hereditary mixed
polyposis syndrome. Presenting Author: Michele Caroline Gornick, University
of Michigan, Ann Arbor, MI
Background: Rare monogenic disorders are often due to mutations that are
highly penetrant, extremely rare, and strongly disrupt normal biology.
Hereditary mixed polyposis syndrome (HMPS, OMIM ID %601228), is
characterized by a mixture of atypical juvenile polyps, hyperplasic polyps,
sessile serrated adenomas and an increased risk of colorectal cancer.
Polyps appear to be inherited in an autosomal dominant fashion. The
putative susceptibility locus initially mapped to 15q13-14, however, the
genetic basis of this syndrome is not well understood, and no mutation or
associated variants have been identified. Methods: Germline DNA from four
individuals from a family with clinically and pathologically confirmed
HMPS was subjected to massively parallel sequencing (Illumina GAII).
Affected individuals had an average of 30x coverage of their exome and 10x
coverage of their genome. Sequence calls were filtered using the criteria of
� 4x coverage, quality score over depth � 50, depth of coverage � 360,
allele balance � 0.75, number or MAPQ zero reads at locus � 4. Common
variants were filtered out by excluding variants found in dbSNP (build131),
1000 Genomes Project, the Exome Variant Server or 80 unaffected
controls sequenced by hybrid capture and whole exome sequencing.
Polyphen2 and SIFT were used to predict pathogenicity of the novel, shared
variants, and validated by Sanger sequencing. Expression levels of novel
variants were examined in available tumor samples using qRT-PCR.
Results: From the 32 previously unidentified nonsense, missense or splice
site variants shared by the family members whose whole genomes were
sequenced, only 5 (4 missense, 1 nonsense) were predicted to be
damaging, leading to a small subset of novel candidate genes including
ZNF426, which may be responsible for HMPS within this family.
Conclusions: HMPS extremely difficult to accurately diagnosis and the
genetic basis is unknown. Using next-generation sequencing we were able
to detect previously unidentified low frequency allelic variants including a
novel candidate locus.
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