scholarly journals Defining the Spectrum, Treatment and Outcome of Patients With Genetically Confirmed Gorlin Syndrome From the HIT-MED Cohort

2021 ◽  
Vol 11 ◽  
Author(s):  
Katja Kloth ◽  
Denise Obrecht ◽  
Dominik Sturm ◽  
Torsten Pietsch ◽  
Monika Warmuth-Metz ◽  
...  

Gorlin syndrome is a genetic condition associated with the occurrence of SHH activated medulloblastoma, basal cell carcinoma, macrocephaly and other congenital anomalies. It is caused by heterozygous pathogenic variants in PTCH1 or SUFU. In this study we included 16 patients from the HIT2000, HIT2000interim, I-HIT-MED, observation registry and older registries such as HIT-SKK87, HIT-SKK92 (1987 – 2020) with genetically confirmed Gorlin syndrome, harboring 10 PTCH1 and 6 SUFU mutations. Nine patients presented with desmoplastic medulloblastomas (DMB), 6 with medulloblastomas with extensive nodularity (MBEN) and one patient with classic medulloblastoma (CMB); all tumors affected the cerebellum, vermis or the fourth ventricle. SHH activation was present in all investigated tumors (14/16); DNA methylation analysis (when available) classified 3 tumors as iSHH-I and 4 tumors as iSHH-II. Age at diagnosis ranged from 0.65 to 3.41 years. All but one patient received chemotherapy according to the HIT-SKK protocol. Ten patients were in complete remission after completion of primary therapy; four subsequently presented with PD. No patient received radiotherapy during initial treatment. Five patients acquired additional neoplasms, namely basal cell carcinomas, odontogenic tumors, ovarian fibromas and meningioma. Developmental delay was documented in 5/16 patients. Overall survival (OS) and progression-free survival (PFS) between patients with PTCH1 or SUFU mutations did not differ statistically (10y-OS 90% vs. 100%, p=0.414; 5y-PFS 88.9% ± 10.5% vs. 41.7% ± 22.2%, p=0.139). Comparing the Gorlin patients to all young, SHH activated MBs in the registries (10y-OS 93.3% ± 6.4% vs. 92.5% ± 3.3%, p=0.738; 10y-PFS 64.9%+-16.7% vs. 83.8%+-4.5%, p=0.228) as well as comparing Gorlin M0 SKK-treated patients to all young, SHH activated, M0, SKK-treated MBs in the HIT-MED database did not reveal significantly different clinical outcomes (10y-OS 88.9% ± 10.5% vs. 88% ± 4%, p=0.812; 5y-PFS 87.5% ± 11.7% vs. 77.7% ± 5.1%, p=0.746). Gorlin syndrome should be considered in young children with SHH activated medulloblastoma, especially DMB and MBEN but cannot be ruled out for CMB. Survival did not differ to patients with SHH-activated medulloblastoma with unknown germline status or between PTCH1 and SUFU mutated patients. Additional neoplasms, especially basal cell carcinomas, need to be expected and screened for. Genetic counselling should be provided for families with young medulloblastoma patients with SHH activation.

2019 ◽  
Vol 2019 ◽  
pp. 1-5
Author(s):  
Gustav Askaner ◽  
Ulrikke Lei ◽  
Birgitte Bertelsen ◽  
Alessandro Venzo ◽  
Karin Wadt

Gorlin syndrome is mainly caused by pathogenic germline variants in the tumour suppressor genes PTCH1 and SUFU, both regulatory genes in the hedgehog pathway. However, the phenotypes of patients with PTCH1 and SUFU pathogenic variants seem to differ. We present a family with a frameshift variant in the SUFU gene c.954del, p.Asn319Thrfs∗42 leading to meningiomas and multiple basal cell-carcinomas.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10512-10512
Author(s):  
Felipe Batalini ◽  
Russell Madison ◽  
Dean C. Pavlick ◽  
Ethan Sokol ◽  
Tamara Snow ◽  
...  

10512 Background: PARPi are approved for treatment of pts w/ HER2-negative mBC and germline BRCA1/2 (g BRCA) pathogenic or likely pathogenic variants (muts); however, clinical benefit has also been demonstrated in mBC pts w/ sBRCA or other HR-pathway gene muts. Using a RW Clinico-Genomic Database (CGDB), we assessed outcomes for pts w/ gBRCA muts compared to pts w/ either s BRCA or other HR-pathway muts treated w/ PARPi. Methods: 6,329 mBC pts from ̃280 US cancer clinics were included in the Flatiron Health (FH) -Foundation Medicine (FM) CGDB, which includes comprehensive genomic profiling (CGP) linked to de-identified, electronic health record (EHR)-derived clinical data. Eligible pts had mBC, received care in the FH network from 1/1/2011-9/1/2020, and had tissue CGP by FM. Pts classified as gBRCA: positive germline result in EHR and BRCA mut predicted germline per FM’s somatic, germline, zygosity algorithm (SGZ) (Sun et al PMID 29415044). Non-g BRCA: negative germline results in EHR and a somatic BRCA (s BRCA) mut per SGZ or BRCA wild-type w/ another HR mut per CGP result. Pts w/o a documented gBRCA result in EHR, unknown FM BRCA SGZ result, or conflicting results were excluded. RW overall survival (rwOS) and RW progression-free survival (rwPFS) from start of PARPi for pts w/ gBRCA and non- gBRCA mBC were compared using Kaplan-Meier analysis and Cox regression adjusted for mBC line number, prior platinum, age at PARPi initiation, race, and receptor status. Results: Among pts who received PARPi in the mBC setting, 44 had gBRCA and 18 had non -gBRCA: 9 s BRCA (5 BRCA1, 4 BRCA2), 4 PALB2, 2 ATM, and 1 each of ATM+CDK12, BARD1+FANCF+RAD54L, and CHEK2. Of HR muts 76% were confirmed biallelic: 33/44 gBRCA (11 unknown), 8/9 sBRCA, 3/4 PALB2, and 3/5 other (1 unknown). Neither median rwPFS nor rwOS from start of PARPi were significantly different between the non-g BRCA and g BRCA cohorts (rwPFS: 7.0 [4.6-11.3] vs 5.5 [4.3-7.2] months (mos), aHR: 1.19 [0.57 – 2.43]; rwOS: 15.0 [7.95-16.3] vs 11.5 [9.46-NA] mos, aHR: 0.85 [0.36-1.98]). For 9 pts w/ sBRCA mut, median rwPFS was 7.1 mos (range 1.4-12.4) and all pts had progressed by data cut off. Conclusions: Despite small pt numbers and limitations from RW data, our results suggest that pts w/ biallelic non-g BRCA mBC may derive similar benefit from PARPi when tumor CGP detects a s BRCA mut or germline or somatic mut in other HR-pathway genes. These findings are consistent w/ the results from TBCRC-048 (Tung et al PMID 33119476) and support further randomized trials exploring the efficacy of PARPi in this population.[Table: see text]


2016 ◽  
Vol 20 (3) ◽  
pp. e40-e41 ◽  
Author(s):  
Emily Kirkpatrick ◽  
Dwina Dobriansky ◽  
James Scurry

2015 ◽  
Vol 33 (24) ◽  
pp. 2675-2682 ◽  
Author(s):  
David M. Gershenson ◽  
Diane C. Bodurka ◽  
Karen H. Lu ◽  
Lisa C. Nathan ◽  
Ljiljana Milojevic ◽  
...  

Purpose Low-grade serous carcinoma of the ovary (LGSOC) or peritoneum (LGSPC) is a rare subtype of ovarian or peritoneal cancer characterized by young age at diagnosis and relative resistance to chemotherapy. The purpose of this study is to report our updated experience with women diagnosed with LGSOC or LGSPC to assess the validity of our original observations. Patients and Methods Eligibility criteria for patients from our database were: stage I to IV LGSOC or LGSPC, original diagnosis before January 2012, and adequate clinical information. All patients were included in progression-free survival, overall survival, and multivariable Cox regression analyses. A subset analysis was performed among patients with stage II to IV low-grade serous carcinoma treated with primary surgery followed by platinum-based chemotherapy. Results We identified 350 eligible patients. Median progression-free survival was 28.1 months; median overall survival was 101.7 months. In the multivariable analysis, compared with women age ≤ 35 years, those diagnosed at age > 35 years had a 43% reduction in likelihood of dying (hazard ratio, 0.53; 95% CI, 0.37 to 0.74; P < .001). Having disease present at completion of primary therapy was associated with a 1.78 increased hazard of dying compared with being clinically disease free (P < .001). Similar trends were noted in the smaller patient cohort. In this cohort, women with LGSPC had a 41% decreased chance of dying (hazard ratio, 0.59; 95% CI, 0.36 to 0.98; P = .04) compared with those with LGSOC. Conclusion Women age < 35 years with low-grade serous carcinoma and those with persistent disease at completion of primary therapy have the worst outcomes. Patients with LGSPC seem to have a better prognosis than those with LGSOC.


2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Elizabeth A. Jones ◽  
Mohammed Imran Sajid ◽  
Andrew Shenton ◽  
D. Gareth Evans

Gorlin syndrome (Naevoid Basal Cell Carcinoma Syndrome) is a rare autosomal dominant syndrome caused by mutations in thePTCHgene with a birth incidence of approximately 1 in 19,000. Patients develop multiple basal cell carcinomas of the skin frequently in early life and also have a predisposition to additional malignancies such as medulloblastoma. Gorlin Syndrome patients also have developmental defects such as bifid ribs and other complications such as jaw keratocysts. We studied the incidence and frequency of basal cell carcinomas in 202 Gorlin syndrome patients from 62 families and compared this to their gender and mutation type. Our data suggests that the incidence of basal cell carcinomas is equal between males and females and the mutation type cannot be used to predict disease burden.


2020 ◽  
Author(s):  
Qinghong Hu ◽  
Abha Hada ◽  
Liping HAN

Abstract Objectives: We sought to determine the impact of pretreatment plasma platelet levels, dimerized plasmin fragment (D-dimer) and fibrinogen in recurrent epithelial ovarian cancer (EOC) and the impact of platelet levels on SKOV3 cell lines growth and responsiveness to chemotherapy.Methods: Under approval of ethical committee, we identified 104 women with recurrent EOC who underwent treatment between January 2010 and February 2015. Reviewing clinical, laboratory, and pathologic records from this retrospective cohort, we analyzed the correlation between pretreatment plasma D-dimer, fibrinogen, platelet levels and clinicopathological parameters, progression free survival (PFS)and overall survival (OS). Inco-culture experiments human ovarian cancer SKOV3 cell lines were used to test the effect of platelet levels on tumor growth and responsiveness to docetaxel.Results: Of the 104 recurrent EOC, thrombocytosis at diagnosis and the decrease of platelet count by less than 25% after primary therapy were associated with worse median progression free survival (P=0.003;P=0.021) and median overall survival (P = 0.009;P=0.009).Mean platelet levels declined at the end of primary therapy(P<0.001) and rose at recurrence(P=0.007) .In multivariate analysis, elevated platelet levels at primary therapy and the decrease of platelet count less than 25% after primary therapy were unfavorable prognostic factor for PFS( P=0.022; P=0.015) and OS(P=0.013;P=0.007)in recurrent EOC, but elevated plasma D-dimer and fibrinogen were not. In SKOV-3 ovarian cancer cell lines, suitable concentration platelet co-culture protected against apoptosis (P< 0.05).Conclusions: Platelet count during treatment could be used as a biomarker used for monitoring the disease recurrence and predicting treatment response. And platelet with suitable concentration co-culture protected against apoptosis in SKOV3 cell line, which may explain clinical observations.


2009 ◽  
Vol 21 (6) ◽  
pp. 502-508 ◽  
Author(s):  
J. Loncaster ◽  
R. Swindell ◽  
F. Slevin ◽  
L. Sheridan ◽  
D. Allan ◽  
...  

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Shoko Onodera ◽  
Nana Morita ◽  
Yuriko Nakamura ◽  
Shinichi Takahashi ◽  
Kazuhiko Hashimoto ◽  
...  

Abstract Background Basal cell carcinoma (BCC) is the most commonly occurring neoplasm in patients with Gorlin syndrome. It is widely accepted that multiple basal cell carcinomas simultaneously develop in middle-aged patients with this syndrome. However, the presence of driver genes other than the PTCH1 in Gorlin syndrome has not been explored. This study aimed to identify common gene mutations other than PTCH1 in simultaneously occurring basal cell carcinomas in patients with Gorlin syndrome via exome sequencing analysis. Methods Next-generation sequencing analysis was performed using four basal cell carcinoma samples, one dental keratinocyte sample, and two epidermoid cyst samples, which were surgically resected from one patient with Gorlin syndrome on the same day. Results Overall, 282 somatic mutations were identified in the neoplasms. No additional somatic mutations in PTCH1, PTCH2, TP53, and SMO were identified. However, enrichment analysis showed that multiple genes, such as IFT172 and KIFAP3, could regulate ciliary functions important for Hedgehog signaling. Conclusion The development of BCCs in patients with Gorlin syndrome may be triggered by mutations that cause substantial dysfunction of cilia.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16526-e16526
Author(s):  
E. Tominaga ◽  
H. Tsuda ◽  
T. Arao ◽  
S. Nishimura ◽  
T. Chiyoda ◽  
...  

e16526 Background: The purpose of this study was to identify genes that predict the progression free survival (PFS) of advanced epithelial ovarian cancer (aEOC) receiving standard therapy. Methods: We performed expression analysis using GeneChip (Human Genome U133 plus 2.0 Array) in aEOC cells produced by laser-based microdissection. Thirty three aEOC patients (stage IIc: 4, III: 19, IV: 10; serous adenocarcinoma: 21, endometrioid adenocarcinoma: 5, undifferentiated: 7) were included in this array study. All cases received staging laparotomy, cytoreductive surgery, and adjuvant chemotherapy (carboplatin + paclitaxel) as primary therapy. Results: Class comparison analysis between groups of NED (no evidence of disease) and non-NED identified 46 genes that exhibited significant differences (p < 0.001). Among them, 6 (13%) genes are located in 8q24 and 9 (19.6%) genes are located in 20q11–13. Finally, we focused on 8q24 and 20q11–13 loci, and confirmed array data using real-time quantitative PCR in 94 validation sets. The validation showed that ZNF7, MAF1, ADRM1, and GNAS amplification was related with PFS (p < 0.05, respectively). Conclusions: The amplification of 8q24 and 20q11–13 can predict the PFS of aEOC and these genes may be new biomarkers for aEOC. No significant financial relationships to disclose.


Sign in / Sign up

Export Citation Format

Share Document