Background
Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis.
Methods
To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined
BAP1
mutation and copy number status and its relationship to immune checkpoint inhibitor activation.
Results
We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of
BAP1
. To further investigate the role of
BAP1
, we used our recently developed cancer driver gene prioritization algorithm, HIT’nDRIVE, and observed that PeM with
BAP1
haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies.
Conclusions
Our findings reveal
BAP1
to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification.
BAP1
stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which
BAP1
status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients.
Electronic supplementary material
The online version of this article (10.1186/s13073-019-0620-3) contains supplementary material, which is available to authorized users.
A cohort of patients with DM who underwent colorectal resection (April 2001-May 2006) at our institution were reviewed. SSI were defined by Centers for Disease Control criteria. From a study cohort of 149 patients, 24% had poor postoperative glycemic control (defined as a mean 48-h postoperative capillary glucose (MCG) >11.0 mmol/L or 200 mg/dL), and these patients developed SSI at a significantly higher rate than those with a 48-h MCG < or =11.0 mmol/L (29.7% vs. 14.3%; odds ratio (OR) 2.5, p = 0.03). On multivariate logistic regression, 48-h MCG >11.0 mmol/L was significantly associated with SSI (OR 3.6, p = 0.02), independent of the dose and regimen of postoperative insulin administration. In conclusion, 48-h MCG >11.0 mmol/L (200 mg/dL) was independently associated with increased SSI following colorectal resection in patients with DM. Prospective studies are required to validate this relationship, address the role of preoperative glycemic control, and examine strategies to improve glycemic control following colorectal resection.
To meet the needs of patients, Canadian surgical and medical oncology leaders in the treatment of peritoneal surface malignancies (psms), together with patient representatives, formed the Canadian HIPEC Collaborative Group (chicg). The group is dedicated to standardizing and improving the treatment of psm in Canada so that access to treatment and, ultimately, the prognosis of Canadian patients with psm are improved.Patients with resectable psm arising from colorectal or appendiceal neoplasms should be reviewed by a multidisciplinary team including surgeons and medical oncologists with experience in treating patients with psm. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy should be offered to appropriately selected patients and performed at experienced centres.The aim of this publication is to present guidelines that we recommend be applied across the country for the treatment of psm.
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