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

10520 Poster Discussion Session (Board #13), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Reproducibility, performance, and clinical utility of a genetic risk prediction
model for prostate cancer in Japanese patients. Presenting Author:
Shusuke Akamatsu, Department of Urology, Kyoto University Graduate
School of Medicine, Kyoto, Japan
Background: Prostate specific antigen (PSA) is widely used as a diagnostic
biomarker for prostate cancer (PC). However, due to its low predictive
performance, many patients without PC suffer from the harms of unnecessary
prostate needle biopsies. The present study aims to evaluate the
reproducibility and performance of a genetic risk prediction model and
estimate its utility as a diagnostic biomarker in a clinical scenario. Methods:
We created a logistic regression model incorporating 16 SNPs that were
significantly associated with PC in a genome-wide association study of the
Japanese. The model was validated by two independent sets of samples
comprising 3,294 cases and 6,281 controls. Various cut offs were
evaluated to be used in a clinical scenario. Results: The area under a curve
(AUC) of the model was 0.679, 0.655, and 0.661 for the samples used to
create the model and those used for validation respectively. The AUC of the
model was not significantly altered in samples with PSA 1-10 ng/ml.
24.2% and 9.7% of the patients had odds ratio �0.5 (low risk) or �2 (high
risk) in the model, and assuming the overall positive rate of prostate needle
biopsies to be 20% in PSA gray zone (PSA 2-10 ng/ml), the positive biopsy
rates were 10.7% and 42.4% respectively for the two genetic risk groups.
Conclusions: The genetic risk prediction model was highly reproducible,
and its predictive performance was not influenced by PSA. The model could
have a potential to affect clinical decision when it is applied to patients
with gray-zone PSA, which should be confirmed in future clinical studies.
10522 Poster Discussion Session (Board #15), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
The effect of two BRM promoter variants on the risk of stage I/II upper
aerodigestive tract cancers. Presenting Author: Kit Man Wong, University of
Toronto, Toronto, ON, Canada
Background: BRM is a key subunit of the chromatin remodeling complex
SWI/SNF and a putative tumor suppressor gene that is silenced in 15-20%
of many solid tumors (PMID 15722796). Evidence suggests that it is
epigenetically regulated, as two BRM promoter insertion variants (BRM-
741 and BRM-1321) may lead to gene silencing by recruiting histone
deacetylases. The presence of both homozygous BRM-741 and BRM-1321
highly correlate with loss of BRM expression and function in lung tumors,
while increasing smoking-related lung cancer by two-fold (PMID
21478907). Also, the pharmacologic reversal of epigenetic changes of
BRM offers a potential novel therapeutic approach (PMID 21478905). We
assessed whether these BRM variants are associated with the risk of upper
aerodigestive tract cancers, focusing on Stage I/II tumors that would most
benefit from new screening and prevention strategies. Methods: BRM was
genotyped by qPCR using TaqMan probes. 1,008 controls were matched to
595 cases by frequency distribution based on age, gender and smoking
status. Multivariate logistic regression generated adjusted odds ratios
(aOR). Results: The 595 cases were: 115 esophageal, 278 lung, and 202
head and neck cancers. 51% were adenocarcinomas; 60% were Stage I.
The frequency of homozygozity was: BRM-741, 26%; BRM-1321, 23%;
both variants, 15%. In the combined analysis, there was significant
correlation between malignancy and homozygous BRM-741 (aOR 1.91
(95%CI 1.3-2.4); p�0.001) or BRM-1321 (aOR 1.94 (95%CI 1.4-2.7;
p�3x10E-4). Being homozygous for both BRM variants carried an even
greater risk (aOR 2.45 (95%CI 1.6-3.9); p�1x10E-5). This correlation was
similar for adenocarcinomas (aOR 2.53 (95%CI 1.4-4.2); p�6x10E-4)
and squamous cell carcinomas (aOR 2.33 (95%CI 1.3-4.4); p�8x10E-4).
The increased cancer risk was also similar between these subgroups: head
and neck, esophageal and lung cancers; Stage I and II patients; smokers
and non-smokers. Conclusions: The two homozygous BRM variants increase
the risk of early stage upper aerodigestive tumors by more than two-fold
independent of smoking status. BRM promoter variants and their potential
epigenetic effect may be early events in the evolution of these cancers.
Tumor Biology
661s
10521 Poster Discussion Session (Board #14), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
BAP1: The first mutated gene causing familial uveal melanoma. Presenting
Author: Johan Hansson, Department of Oncology-Pathology, Stockholm,
Sweden
Background: Uveal melanoma (UM) is a rare malignancy with a poor
prognosis. Familial predisposition to UM is rare and accounts for only a few
percent of all cases. The genetic background of hereditary UM is unknown
and the aim of our project was to identify susceptibility gene(s) for UM.
Methods: We identified a family with hereditary predisposition for UM – the
proband of which is a young female diagnosed with UM at age 16 who
within 6 months developed liver metastases. We also identified two older
paternal relatives who were diagnosed with UM at 39 and 44 years of age,
respectively. We performed massively parallel sequencing using the Illumina
Hiseq2000 technology on germline DNA from the proband, her
parents and a healthy sibling. After QC and mapping against the human
reference genome the average coverage across the exome was between 35
and 86 for the four sequenced samples. Results: Out of more than 260,000
single nucleotide variants (SNVs) and small insertion / deletion variants
(indels), 51 gene variants were filtered out by being novel, shared by the
affected proband and her father (considered an obligate mutation carrier),
but not by the healthy mother, of predicted functional importance and /or
located within strongly conserved regions. The strongest candidate among
these was a loss of function-variant in the BAP1 gene, since BAP1 has been
suggested as a tumor suppressor in several cancer-related syndromes,
including cases of UM. The sequence data indicated an insertion of one
base-pair in exon 3 of the BAP1 genecausing a frame-shift and subsequently
a truncated protein lacking all its functional domains. The
mutation was also present in UM tumor tissue from the two deceased
paternal relatives and was found to segregate with the UM phenotype in the
family. We also detected loss of heterozygosity in the tumor of the proband,
supporting BAP1 as the causative gene in this family. Conclusions: The
identification of BAP1 as the gene responsible for this syndrome is the first
demonstration of a germline mutation causing UM. This enables us to
identify and monitor risk individuals belonging to mutation positive
families with predisposition to UM, and possibly other cancer syndromes.
We are continuously screening other cases of familial UM for mutations in
BAP1.
10523 Poster Discussion Session (Board #16), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Prognostic significance of LINE-1 methylation level in the upper gastrointestinal
cancer. Presenting Author: Yoshifumi Baba, Kumamoto University,
Kumamoto, Japan
Background: Genome-wide DNA hypomethylation plays a role in genomic
instability and carcinogenesis. DNA methylation in long interspersed
nucleotide element-1 (LINE-1) is a good indicator of global DNA methylation
level. Although LINE-1 methylation level is attracting interest as a
useful marker for predicting cancer prognosis, the prognostic significance
of LINE-1 hypomethylaiton in the upper gastrointestinal cancer [i.e.,
esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC)]
remains unclear. Methods: Using 217 ESCC and 207 GC specimens, we
quantified the LINE-1 methylation using bisulfite-pyrosequencing technology.
During the follow-up, there were a total of 63 ESCC recurrences, 51
ESCC deaths and 56 GC deaths. The median follow-up time for censored
patients was 2.8 years. A Cox proportional hazards model was used to
calculate the hazard ratio (HR), adjusted for the clinical, epidemiological,
and pathological variables. The term “prognostic marker” is used throughout
this study according to the REMARK Guidelines. Results: ESCCs and
GCs showed significantly lower LINE-1 methylation levels compared to
matched normal mucosa (p�0.0001). In ESCC, LINE-1 hypomethylation
was significantly associated with disease-free survival [log-rank p�0.0008;
univariate HR� 2.32, 95% confidence interval (CI) 1.38-3.84, p�0.0017;
multivariate HR�1.81, 95% CI 1.06-3.05, p�0.031] and cancer-specific
survival (log-rank p�0.0020; univariate HR�2.21, 95% CI 1.33-3.60,
p�0.0026; multivariate HR�1.87, 95% CI 1.12-3.08, p�0.018]. We
found a significant modifying effect of the tumor stage on the relationship
between LINE-1 methylation and the recurrence rate (P for interaction �
0.031). In GC, LINE-1 hypomethylation was significantly associated with
cancer-specific survival (log-rank p�0.029; univariate HR�2.01, 95% CI
1.09-3.99). Conclusions: LINE-1 hypomethylation is associated with shorter
survival in both ESCC and GC, suggesting that it has potential for use as a
prognostic biomarker.
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