Active Projects

What we’re working on right now….


Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women below age 40, with a mean diagnosis age of 23.9 years. It is an extremely aggressive tumor and, due to lack of effective treatment, long-term survival rates are poor. By performing whole exome sequencing on 3 families with multiple members affected by SCCOHT, we recently discovered that inherited mutations in SMARCA4 were segregating with the disease in these families. Sequencing of additional tumors, familial and sporadic in origin, revealed that all had loss of SMARCA4 expression resulting either from mutations or loss of heterozygosity, identifying SCCOHT as a monogenic disease. This discovery was published in Nature Genetics in May 2014 (Witkowski et al, Nat Genet 2014; 46(5):438-43).

To follow up on these findings, we are now studying the methylomes and transcriptomes of SCCOHT tumors and cell lines to identify critical SMARCA4 target genes/networks. In a collaboration with Dr. Sidong Huang from the Biochemistry department at McGill, we are using SCCOHT cell lines as a model system to uncover synthetic lethal interactions with SMARCA4 loss via large-scale screening of small compound and shRNA libraries. Our ultimate goal is to identify genes and/or chemical compounds that can be used to treat this disease more effectively.

Breast cancer predisposition genes

Breast cancer is the most prevalent cancer among women, and approximately 10% of all breast cancers are hereditary. The two best known breast cancer susceptibility genes, BRCA1 and BRCA2, were identified 20 years ago, but mutations in these genes account for ~40% of inherited breast cancers. Since then, other genes including ATM, BARD1, BLM, BRIP1, CHEK2, NBS1, PALB2, PTEN, RINT1, TP53 and XRCC2 have been proposed as candidate breast cancer susceptibility genes and together account for another ~10% of hereditary breast cancer families. However, the genes responsible for the other 50% of hereditary cases are yet to be identified.

Certain populations like the French Canadian population of Quebec are notable for the presence of founder mutations that are the result of their presence in a small number of original settlers. Our team has contributed significantly to the identification, characterization and clinical application of founder mutations in BRCA1, BRCA2 and, most recently, PALB2. Identification of these founder mutations has greatly facilitated genetic screening of at risk families in Quebec through the use of low-cost, targeted screening assays.

Worldwide, there have been intense efforts to identify the missing breast cancer susceptibility genes, but it is becoming clear that the remainder of the “missing heritability” for breast cancer in outbred populations cannot be attributed to a small number of undiscovered moderate to high penetrance breast cancer susceptibility genes, and progress has been slow. However, in founder populations, a single allele can contribute substantially to the burden of disease attributable to a given gene. In this project, we take advantage of the founder status of the Quebec population and use the latest next generation sequencing technologies to search for predisposing genetic lesions in high risk French Canadian breast cancer families without identified mutations in known breast cancer susceptibility genes.

DICER1 pleiotropic tumour syndrome

In 2009, the association of germline DICER1 mutations with a distinctive human disease syndrome (OMIM 601200) involving familial pleuropulmonary blastoma was reported. Since then, germline DICER1 mutations have also been described in cystic nephroma, embryonal rhabdomyosarcomas, ovarian sex cord stromal tumors (especially Sertoli-Leydig cell tumors), nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, multinodular goiter, differentiated thyroid carcinoma, Wilms tumor, pituitary blastoma and pineoblastoma, among others. Since 2009, our group contributed several manuscripts to the description of the DICER1 mutations and associated phenotypes in affected families.

More recently, our work on this syndrome has extended to the identification of somatic mutations in DICER1 tumors. There is mounting evidence to support the notion that, unlike the situation with oncogenes or classical tumor suppressor genes, DICER1-related tumor development relies on a delicate balance of germ-line and somatic lesions that compromise the microRNA processing function of the enzyme while in most cases avoiding its complete loss. Several on-going projects in our laboratory using patient tumors and model systems aim at elucidating the molecular events required for tumor development in carriers of hereditary DICER1 mutations.

We have started the first Canadian research network for the study of DICER1 Syndrome. With the purpose of collecting more information about DICER1 Syndrome, we have started a website where we share information about DICER1 Syndrome. Our database is being shared with interested parties free of cost.

Inherited colorectal cancers

Hereditary colorectal cancer represents approximately 5-10% of all colorectal cancer cases, and the risk of cancer in these families is high. Germ-line mutations in the DNA mismatch repair genes MLH1, MSH2, PMS2, and MSH6 are known to predispose to inherited colorectal cancer, as do biallelic mutations in the MUTYH gene. However, a significant number of families remain where the results of genetic testing revealed no mutations in these genes.

In this project, we aim to identify novel, highly penetrant susceptibility genes for colorectal cancer using the latest sequencing technologies available. Three groups of patients that are often seen in a clinical genetics setting and who are at high risk of genetic predisposition are being targeted for gene discovery efforts: patients who developed > 50 adenomatous polyps, patients diagnosed with early-onset colorectal cancer before age 25, irrespective of family history and, finally, high risk familial cases with at least 3 closely related confirmed  cases of colorectal cancer.

This project is part of a collaboration between our group and the research team of Dr. Gabriel Capella in Barcelona, Spain. Both the Catalan and Québec populations are founder populations in which founder mutations have been identified in other cancer predisposition genes. Our strategy to focus on founder populations will improve our chances of identifying recurrent mutations in each population while using the other population for validation of the candidate genes identified.

Spindle Assembly Checkpoint genes

The spindle assembly checkpoint is a ubiquitous control mechanism present in all eukaryotes that ensure correct chromosome segregation and the successful delivery of a euploid chromosome set to each daughter cell during mitosis. Several of these genes have been found to be mutated somatically in colorectal cancers and our group recently reported on a germ-line mutation in a spindle assembly checkpoint gene, BUB1B, which resulted in multiple malignancies of the gastrointestinal tract in a homozygous mutation carrier (Rio Frio et al N Engl J Med 2010 363, 2628-37).

This project follows from this report and aims at exploring the role of inherited mutations in spindle assembly checkpoint mutations in cancer development using multiple approaches, including re-sequencing of tumors, allelic imbalance studies and functional experiments in cellular models. 

Rare familial tumors

Families with multiple members affected by rare or unusual cancer phenotypes provide valuable opportunities to study the genetic factors underlying these disorders. Such families occasionally come to the attention of our research group through the clinical genetics work of our PI. One such case was a patient with multiple gastrointestinal lesions who proved to be a carrier of a biallelic mutation in BUB1B. Our discoveries about his genetic lesion provided the basis of our subsequent research projects on spindle assembly checkpoint genes. Another example was our work on 3 families with familial SCCOHT. Our findings from these families showed that genetic factors predisposing to rare hereditary versions of these tumors can also be involved in the etiology of the more frequent, sporadic versions of the disease, resulting in another long-term research project.

Identifying predisposing mutations in a single family can be challenging, but the advent of next generation sequencing technologies has greatly facilitated the process. In collaboration with research groups at our local core facility, the McGill University and Genome Quebec Innovation Center, we have worked to optimize exome sequencing of formalin-fixed, paraffin-embedded tumors. We are now able to compare the exomes from the germ-line and the tumors of individual patients, thus enabling us to observe the genetic changes involved in the molecular evolution of tumor cells. We have collected several families with rare hereditary cancer phenotypes from the clinic and from the literature that are currently under investigation in our laboratory. Our most recent success story was the discovery that FGFR1 abnormalities play a role in both familial and sporadic neuroepithelial tumors commonly referred to as DNETs.