Molecular tumour pathology - and tumour genetics

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Pathology.

Aim and focus

Program 30902 ultimately aims to deliver personalized medicine for the treatment of bone‐ and soft tissue tumours, female cancers, colorectal cancer and endocrine tumours. The whole pipeline from bench to bedside is covered with special focus on cancer genetics, immunotherapy and molecular therapeutics. Specific objectives are

  • to identify diagnostic and predictive markers as well as novel drug and immunotherapy targets, tumours are characterized at the genomic, expression and immunophenotypical level, after which the functional relevance of the identified molecular alterations is evaluated using several in vitro and in vivo models (including stem cells, cell lines, 3D culture, reporter constructs, zebrafish, and genetically modified as well as xenografted mice). Clinical translation is secured  by the validation of promising markers in high quality tissue repositories. 
  • to detect and characterise novel germline defects for hereditary cancer, using deep‐sequencing, association and mutation analyses in large (familial) patient cohorts and molecular classification profiles in cancer prone families.
  • to rapidly implement results in molecular diagnostics as well as in clinical trial design.

Position in international context

Collaboration within European consortia such as EEC, ENCCA, BRIDGES, and EuroSARC (EC granted networks of excellence), ENITEC, TransPORTEC, EORTC, EOI, BCAC, ENIGMA, COGENT, FAST‐SEQ and CIMBA. Substantial input is being given to the classification and genetics program of the WHO.

Content / highlights / achievements

Bone and soft tissue tumours

  • Unravelling the mechanism of IDH mutations in the development of enchondroma. In chondrosarcoma we showed that IDH mutations are not correlated to outcome and are not essential for tumorigenesis.
  • Identification of novel therapeutic targets in sarcomas (e.g. survivin, Bcl-XL in chondrosarcoma, Bcl-2 family members in leiomyosarcoma, survivin in myxoid liposarcoma).
  • Characterization of the immune microenvironment in different tumour types (e.g. osteosarcoma, chondrosarcoma).
  • Implementation and validation of novel diagnostic tools (e.g. H3F3 mutation analysis in giant cell tumour of bone and chondroblastoma, H3K27me3 loss in MPNST).
  • Identification of novel biomarkers using imaging mass spectrometry (e.g. PSME1 in leiomyosarcoma).

Female cancers

  • Establishment of clinical significance of POLE mutant endometrial cancers and the underlying mechanisms explaining its indolent behaviour.
  • Establishment for the first time of the prognostic relevance of the TCGA molecular classification of endometrial cancer, forming the basis of the first clinical trial with molecular analysis as an integral part (PORTEC-4a)
  • Establishment of the molecular heterogeneity of grade 3 endometrioid endometrial cancers and its clinical significance
  • First in depth genetic characterisation of vulvar cancer and establishing the clinical significance of non-HPV related vulvar cancers.

Breast and colorectal cancer

  • Development of genetic and functional approaches to assess the pathogenicity of DNA variants of unknown clinical significance in breast and colorectal cancer genes. 
  • Low penetrant modifiers of breast and colorectal cancer risk were identified; their joint (polygenic) effects in familial cases studied and for some, the likely causal variants were identified.

Colorectal cancer

  • Elucidation of the genetic burden of unexplained suspect Lynch syndrome EC , CRC and colonic polyposis. In a subset of suspect Lynch cases underlying somatic MMR variants in combination with germ line or somatic pathogenic variants in POLE/D1 were found. For polyposis specific patterns of APC mosaicism was identified.
  • SNP‐array CGH profiles from CRC predisposing syndromes reveal a unique type of genomic instability and point to yet unidentified germline defects in familial colorectal cancer. DNA repair-deficient cancers display an immune evasive phenotype that is related to prognosis.

Endocrine tumours

  • Several new genes were discovered as playing a role in the tumorigenesis of hereditary paraganglioma, some potentially providing a molecular explanation for the parent-of-origin-dependent inheritance in some families. 
  • In parathyroid cancer exome sequencing revealed novel molecular insights for this rare cancer.

Future themes

  • Cancer genetics: precision medicine is dependent on an accurate diagnosis combined with knowledge on the underlying molecular background. At the somatic level, the focus will be on recurrent genetic alterations and unravelling their downstream pathways. For this, stem-cell based models will be generated for osteosarcoma, chondrosarcoma and vascular tumors (VICI grant Bovée). The molecular classification of endometrial cancers improves prognostication and will change practice when we validate our recent findings (Young Investigator Grant Bosse). The mechanisms of tumorigenesis in endocrine tumours (thyroid carcinomas and SDHD‐linked paragangliomas) will be further studied. At the germline level, we will translate the role of common, rare, and private DNA variation in genetic susceptibility to breast, endometrial, ovarian and colorectal cancer to the clinic. We will study their interactions in a systems biology approach, combining next‐generation sequencing of DNA and RNA, with functional analyses of in vitro and in vivo models, thereby improving genetic risk profiling to aid tailoring of cancer screening programs towards those that most urgently need it. When available, high quality clinical trial repositories with sound follow-up data will be used for validating promising markers. 
  • Immunotherapy: the investigation of the potential application of neo‐antigen targeted immunotherapy. Unique mutation profiles of tumors will be revealed by next‐generation sequencing and mutated proteins (neo‐antigens) will be tested for their ability to induce anti‐tumour immune responses in autologous T‐cells derived from patients (Young investigator grant and Veni grant de Miranda). The successful stimulation of immune responses would support the employment of neo‐antigens as therapeutic vaccines in these patients. Furthermore, we will evaluate the anti-cancer potential of elusive immune cell subsets using the VECTRA and by applying mass cytometry (CyTOF). 
  • Molecular therapeutics: exploration of options for targeted therapy. Complementary to our own generation of novel, and the use of existing cancer cell lines, 3D cultures from cell lines as well as from primary tumor tissue will be optimized to test whether the pathways identified in (1) can be targeted using existing drugs. Focused compound screens and synthetic lethality screens can be performed to identify drug targets. In vivo (zebrafish, bioluminescent orthotopic mouse model) models are in place to study the efficacy of newly identified drugs. Another focus will be on the role of homologous recombination in different tumor types (endometrial cancer, sarcoma) and sensitivity to PARP inhibition.

Cohesion within LUMC

Program 30902 is embedded within the biomedical focus area “Cancer Pathogenesis and Therapy” (CPT) as well as in the generic focus area “Biomedical imaging”. The 30902 group members participate in the weekly working discussion “Molecular Tumour Genetics” (MTG), and in the “Mutanome” working group on immunotherapy (Sjoerd van den Burg). The chosen tumour types are top referral care for the LUMC, recognized as national centre of excellence and/or embedded in European Reference Networks (EuraCAN). CPT has defined 3 areas where the LUMC has a strong position, nationally. These are cancer genetics, immunotherapy, and molecular therapeutics. The activities described above fit these areas very well, and provide a good basis for 30902 to forge new collaborative activities involving multiple groups in the LUMC. 

We already closely collaborate with the Departments of Human Genetics, Clinical Genetics, Orthopaedic Surgery, Gynaecology, Medical Oncology, Molecular Cell Biology, Medical statistics and Bioinformatics, Paediatrics, Surgery, Otolaryngology, Gastroenterology, Endocrinology, as well as the several technological focus areas of the LUMC (e.g. SASC, LGTC, CPM). Program 30902 is also incorporated in the Leiden university focus areas “Bioscience: the science base of health” and “Translational drug discovery and development”. Moreover, 30902 actively participates in the “Leiden Network for Personalized Therapeutics”.