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Page 20 of 27 J Cancer Metastasis Treat 2019;5:5 I http://dx.doi.org/10.20517/2394-4722.2018.108

Introduction: Malignant Pleural Mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos
exposure. A genetic predisposition has been suggested to explain the occurrence of multiple cases in the
same family and the observation that not all individuals highly exposed to asbestos develop the tumor.
Germline variants in BAP1 are responsible for a rare cancer-prone syndrome (BAP1-TPDS) that includes
mesothelioma in its cancer constellation. CDKN2A and several DNA repair genes have been reported as
further predisposing genes.

Results: We searched for BAP1 germline variants in 25 new probands with suspected BAP1-TPDS and we
found a new pathogenic germline variant that affects splicing: c.783+2T>C. We calculated that the prevalence
of the truncating variants in patients with familial MPM and MPM and other tumors is 7.7% (3/39).
Cumulative asbestos exposure was assessed quantitatively in our cohort of patients to compare patients
carrying pathogenic variants in BAP1, CDKN2A and DNA repair genes (n = 14) to patients without variants
in 94 cancer predisposing genes (n = 67). We showed that patients with variants in BAP1, CDKN2A and DNA
repair genes had a lower asbestos exposure than non-mutated patients (P = 0.00002).

Conclusion: Our results suggest that other genes could be involved in the genetic predisposition to
mesothelioma. These data support the hypothesis of an increased asbestos sensitivity in patients with
germline variants in CDKN2A, BAP1 or DNA repair genes. According to the concept of BRCAness, patients
with germline mutations in genes involved in homologous recombination repair may respond to drugs
(e.g., PARP inhibitors) that induce synthetic lethality, similarly to patients with familial ovarian cancer and
BRCA1/BRCA2 inherited mutations.

27. Resveratrol reverts the EMT phenotype induced by lysophosphatidic acid in ovarian
cancer cells through restoration of autophagy

1
1
1
Alessandra Ferraresi , Christian Seca , Chiara Vidoni , Carlo Girone , Ji Hee Ha , Danny N.
2
1
2
Dhanasekaran , Ciro Isidoro 1
1 Laboratory of Molecular Pathology and Nanobioimaging, Department of Health Sciences, Università del
Piemonte Orientale “A. Avogadro”, Via Solaroli 17, Novara 28100, Italy.
2 Stephenson Cancer Center and Department of Cell Biology, The University of Oklahoma Health Sciences
Center, Oklahoma City, OK 73104, USA.
Introduction: Ovarian cancer emerges as a highly aggressive metastatic disease characterized by a high
grade of lethality due to its asymptomatic nature and the late diagnosis, when cancer cells already spread
in distant organs. Cancer progression is facilitated by pro-invasive factors, released by ovarian cancer cells
and CAFs, that promote the Epithelial-to-Mesenchymal transition (EMT). Lysophosphatidic acid (LPA), a
bioactive phospholipid abundantly present in ascitic fluid and plasma of ovarian cancer patients, stimulates
the invasiveness of cancer cells. Resveratrol (RV), a natural-occuring polyphenol, is attracting the interest of
many researchers due to its several anti-cancer properties. Of note, RV is a strong autophagy inducer.

Results: We found that LPA elicits cell migration in a panel of ovarian cancer cell models characterized
by different grades of malignancy. In parallel, LPA induces EMT through the inhibition of autophagy in
the cancer cells at the migration front. Interestingly, RV restores autophagy and halts ovarian cancer cell
motility even in the presence of LPA.

Conclusion: Our findings indicate that restoration of autophagy by RV prevents LPA-induced tumor invasion
and suggest that there is a functional cross-talk between autophagy and EMT phenotype.