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

1539 General Poster Session (Board #1C), Sat, 1:15 PM-5:15 PM
Evaluation of genes associated with undescended testes as predictors of
TGCT susceptibility. Presenting Author: Ariela Marshall, Hospital of the
University of Pennsylvania, Philadelphia, PA
Background: Testicular germ cell tumors (TGCTs) are highly heritable.
Cryptorchidism (undescended testes; UDT) is a strong risk factor for TGCT,
with increased risk to both the ipsilateral and contralateral testes. However,
recent genome-wide association studies (GWAS) identifying genetic variants
associated with TGCT susceptibility have not found differences in
genotype carriage between TGCT patients with and without UDT. We
investigated the role of potential risk variants for UDT as risk factors for
TGCT. Methods: 1300 SNPs in and around 25 gene regions with published
associations with UDT were evaluated in 474 TGCT cases (45 with UDT)
and 919 controls. Genotype information was available from the Affymetrix
Genome-Wide Human SNP Array 6.0. Statistical analysis was performed
using PLINK, and statistical significance was assessed by Fisher’s Exact
test. Results: Comparing TGCT cases with and without UDT, variants in the
region of four genes (EPHB2, ESR1, SEMA3C, TGFBR3) were suggestively
associated with UDT. When TGCT cases with UDT were compared with
unaffected controls, the associations all met the required level of significance
(p � 4x10-5 ). Only variation at ESR1 approached significance
(P�0.0004) when TGCT cases and unaffected controls were compared.
Conclusions: We identified variants at three genetic loci - SEMA3C,
TGFBR3 and EPHB2 - that were significantly associated with UDT, but not
with TGCT. The association of variation in EPHB2 and SEMA3C with UDT
are novel findings. While associated with UDT, variation at ESR1 is also
potentially associated with TGCT risk. These data continue to suggest that
genetic risk factors for UDT are largely independent of those for TGCT.
Thus, screening for TGCT could be targeted in a UDT population to those
with genetic risk factors. Further studies should be done to investigate the
genetic link between UDT and TGCT.
1541 General Poster Session (Board #1E), Sat, 1:15 PM-5:15 PM
Clinical characteristics of patients with malignant pleural mesothelioma (MPM)
harboring somatic BAP1 mutations. Presenting Author: Marjorie Glass Zauderer,
Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Efforts to elucidate tumorigenic mutations in MPM are essential to
advance therapy. We reported a 23% incidence of somatic mutations in
BRCA1-associated protein-1 (BAP1) in 53 patients with MPM (Bott et al. Nat
Genet 2011). Germline BAP1 mutations were also reported in two families with a
predisposition to mesothelioma and uveal melanoma (Testa et al. Nat Genet
2011). While BAP1 somatic mutations are more common in poor prognosis uveal
melanoma (84% class 2, 4% class 1; Harbour et al. Science 2010), the
significance of these mutations in MPM is unknown. Therefore, we analyzed the
clinical characteristics of patients with somatic BAP1 mutations in order to
describe this newly identified subpopulation. Methods: We reviewed the charts of
121 patients with tumors tested for somatic BAP1 mutations. Results: Patient
characteristics are in the Table. Twenty percent harbored somatic BAP1
mutations. Other than the percent of current or former smokers (75% BAP1
mutations, 42% BAP1 wild-type, p�0.006), no other clinical feature was
significantly different among those with and without BAP1 mutations. Among 53
samples analyzed for NF2 mutation and p16 deletion, no correlation was seen
with BAP1 mutation. Conclusions: Somatic BAP1 mutations occur in about 20%
of MPM tumors. Aside from smoking history, no other differences in clinical
characteristics or outcomes were noted in the BAP1 mutated cases. Similar
efforts are needed to describe the features of germline mutations in order to
define this new cancer predisposition syndrome. We are planning a prospective
trial to further evaluate the prevalence of germline BAP1 mutations, and we are
also exploring the therapeutic implications.
BAP1 mutants
(N�24)
BAP1 wild-type
(N�97) p value
Gender (M � male) M: 79% M: 68% 0.33
Median age at diagnosis 65 63 0.31
Histology
E: 71% E: 77% 0.28
E � epithelial
M: 25% M: 12%
M � mixed
S � sarcomatoid
S: 4% S: 10%
Stage I: 13%
I: 5% 0.43
II: 25% II: 27%
III: 33% III: 45%
IV: 29% IV: 22%
Known asbestos exposure 54% 46% 1
Smoking (former or current) 75% 42% 0.006
Surgery
EPP: 54% EPP: 55% 1
EPP � extrapleural pneumonectomy Other: 38% Other: 35%
None: 8% None: 10%
Median overall survival from
diagnosis (months)
14.8 15.3 0.78
Cancer Prevention/Epidemiology
95s
1540 General Poster Session (Board #1D), Sat, 1:15 PM-5:15 PM
MEN1 gene mutations with different phenotypic presentations in two
families: Is it a time to grade MEN1 mutations as high-risk and low-risk?
Presenting Author: Alexander L. Shifrin, Jersey Shore University Medical
Center, Neptune, NJ
Background: MEN1 syndrome results from MEN1 gene mutations and is
characterized by primary hyperparathyroidism (PHPT), pancreatic endocrine
tumors (PET), pituitary adenomas, thymic and other tumors. About
600 different mutations have been reported on Human Gene Mutation
Database and 30 of them presented as Familial Isolated Hyperparathyroidism
(FIHP); however, no genotype-phenotype correlations have been
identified. Methods: We characterized 2 independent families with newly
diagnosed MEN1. Mutation analyses were performed in Dept of Genetics
Yale University. Diagnostic tests, surgical treatment were implemented.
Results: Family 1 has 21 members. 5 presented with early onset of PHPT
and no other tumors. 3 ½ parathyroidectomies were performed. A proband
had direct sequencing that showed a mutation in Exon 7, consisting of
single base insertion in codon 319 (TAC to TTAC)(c1065_1066insT).
There were no deaths in the family. Family 2 has 20 members. 7 were
tested and showed a mutation in Exon 2, consisting of single base deletion
in codon 103 (CTG to _TG)(c417delC). One 1st generation member died
from PET at age 79, three 3rd generation members had multifocal
metatstatic malignant gastrinomas (ages 32, 39, 41). The proband had
total pancreatectomy at age 32. Five members had PHPT, angiofibromas.
Three 2nd generation members had thymic carcinomas (ages 20, 54, 60).
Conclusions: Phenotypic presentation of MEN1 syndrome may vary with the
same mutation suggesting a lack of genotype-phenotype correlation and
the effect of modifying factors. On the other hand, these two families—one
with a mutation predicted to truncate the menin protein close to its
terminus and the other with a truncating mutation early in the coding
sequence—have dramatically different severity of the syndrome. Our
findings suggest that the exon 7 mutation has a milder effect on protein
function resulting in FIHP. The management may be heavily influenced by
the predicted clinical phenotype, we are proposing the development of a
grading system for MEN1 gene mutations as low-risk and high-risk and to
attempt to identify other modifying genetic and environmental factors to
improve screening and timing for surgery.
1542 General Poster Session (Board #1F), Sat, 1:15 PM-5:15 PM
Genetic testing referral, uptake, and results in a program for women age 40
or younger with breast cancer. Presenting Author: Asma Ali, Sunnybrook
Health Sciences Centre, University of Toronto, Toronto, ON, Canada
Background: PYNK: Breast Cancer Program for Young Woman is a novel
program started in 2008 at our center to optimize management and
promote research for women � age 40 newly diagnosed with breast cancer.
Clinical and epidemiological data including cancer family history (FH) is
prospectively collected on each consenting patient. As Toronto’s population
is uniquely multiethnic we sought to determine BRCA testing eligibility,
uptake and results for PYNK patients. Methods: Of the 145 consecutive
patients, data were available for 109, of whom 2 had testing prior to
diagnosis. Our provincial BRCA testing criteria are age � 35 at diagnosis;
suspicious FH; or Ashkenazi Jewish (AJ) and age � 50 at diagnosis. Results:
Of the 107 previously untested patients, 40 were � 35 at diagnosis. In 5 of
the other 67 testing eligibility could not be assessed. 66 of the 102 (65%)
were eligible and of those 65 (98%) were offered referral for counseling.
One declined counseling, 9 were not yet seen, 2 declined testing, and 53
were tested. Test results are available for 47 as follows: 30 (64%) no
mutation, 4 (8%) variant of uncertain significance (VUS), 7(15%) BRCA1
mutations and 6 (13%) BRCA2 mutations including 1 of the 4 AJ women.
Ethnicity of the other 12 mutation carriers was: 1 Hispanic, 2 European, 2
African, 4 Asians, 1 mix, 1 unknown and 1 not recorded. Two (15%) of the
mutation carriers had no FH of breast or ovarian cancer. Four additional
women opted for counseling and testing despite ineligibility and none had
mutations. Conclusions: A specialized program for young women facilitates
appropriate referral for genetic testing and encourages high testing uptake,
which is important given the high prevalence of mutations (28% of tested
women). Further research is necessary to assess the psychological and
management impact of having a VUS on young women compared to their
older counterparts.
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