William D Foulkes’s research while affiliated with Jewish General Hospital and other places
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Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive cancer affecting young women, driven by inactivating mutations in SMARCA4, a key SWI/SNF chromatin remodeling gene. To uncover its druggable vulnerabilities, we performed a compound screen and found that SCCOHT cells and tumors were sensitive to PARP inhibitors. Paradoxically, SCCOHT displayed BRCA-deficient traits despite retaining wild-type BRCA1 expression. Elevated R-loop in SCCOHT sequestered BRCA1, limiting its availability for DNA damage repair. Proximity-dependent biotin identification revealed that wild-type SMARCA4, but not its pathogenic variants, promoted RNA polymerase II (Pol II) elongation by mediating the assembly of the polymerase-associated factor 1 (PAF1) complex. Thus, SMARCA4 loss increased Pol II pausing, resulting in elevated R-loops and BRCA1 redistribution. The suppression of BRCA1 activity sensitized SMARCA4-deficient SCCOHT cells and tumors to PARP inhibitors, which was further enhanced by the addition of a CDK9 inhibitor targeting Pol II elongation. Co-targeting PARP/CDK9 also elicited synergistic effects against other undifferentiated ovarian cancer cells with SMARCA4 loss. These findings link SMARCA4 loss to perturbed Pol II elongation and compromised DNA repair by BRCA1, providing a therapeutic opportunity to target SCCOHT and other SWI/SNF-deficient ovarian cancers.
Attenuated familial adenomatous polyposis (AFAP) is a disorder caused by germline pathogenic variants in APC and is characterized by the presence of <100 colonic polyps and a high lifetime risk of developing colorectal cancer. Salivary gland basal cell tumours are uncommon and have not been reported in AFAP before. We present a family with AFAP and multiple salivary gland tumours, including basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC). The colon and salivary gland tumours showed abnormal nuclear beta-catenin staining. Genomic analysis of both parotid BCACs showed CNN-LOH at the APC locus, implicating loss of full-length APC in the aetiology of the parotid BCACs. In contrast, the submandibular BCAC showed a p.(Ile35Thr) CTNNB1 mutation. Spatial transcriptomic analysis revealed a stepwise increase in the expression of WNT pathway genes across the proband’s salivary lesions, from benign (intercalated duct hyperplasia and BCA) to malignant (BCACs). Our results showcase BCA and BCAC as new phenotypes of AFAP.
Purpose
While enhanced breast screening of germline pathogenic variant (GPV) carriers results in earlier stage at diagnosis, the impact of tumour biology and GPV on chemotherapy receipt in early-stage disease remains understudied.
Methods
We retrospectively reviewed treatment administered following a first diagnosis of BRCA1/2 - and PALB2 -associated breast cancer between 2002 and 2022. Chemotherapy receipt was compared according to tumor size, biologic subtype, and GPV. Subgroup analyses were performed in women with T1N0 disease and in those with pre-diagnostic awareness of their GPV.
Results
Overall, 309 affected BRCA1/2 and PALB2 carriers with a median age of 43 years at breast cancer diagnosis (range, 19–80 years) were included; 160 (51.8%) BRCA1 , 130 (42.1%) BRCA2 , and 19 (6.1%) PALB2 carriers. Chemotherapy was administered in 70.9% of index breast cancer cases and was significantly associated with younger age, tumor size, histologic grade, nodal status, and biologic subtype (all p < 0.05). Chemotherapy receipt was 80.6% in BRCA1 -associated breast cancers compared to 56.9% in BRCA2 and 84.2% in PALB2 associated breast cancers ( p < 0.001). In subgroup analysis of early stage, T1N0 disease, chemotherapy was administered in 78.9% BRCA1 and 59.5% BRCA2/PALB2 patients ( p = 0.04). Pre-diagnostic awareness of a GPV in BRCA1/2 or PALB2 was associated with smaller invasive tumors (%T1, 50% vs. 32.9%; p = 0.002) and node-negative invasive disease (87.1% vs. 72.2%), as well as a reduced likelihood of chemotherapy (59.7% vs. 74.3%, p = 0.02).
Conclusion
Chemotherapy receipt is high in BRCA1/2 and PALB2 -associated breast cancers including in early stage, node-negative disease. Pre-diagnostic awareness is associated with a lower likelihood of requiring chemotherapy for a breast cancer diagnosis.
The processes that lead to cancer transformation, in particular the clonal evolution that precedes malignancy, remain incompletely understood. Somatic mutations accumulate throughout the life of a cell and are shaped by its epigenetic landscape. We hypothesize that integrating somatic mutational profiles with the epigenetic landscapes of normal cells can explain the distribution of mutations in cancer, provide insights into the relationships between normal and cancer cells, and thus shed light on the cellular origins of cancer. Our study integrates mutation data from more than 25 normal tissue types with epigenetic profiles from over 300 normal cell types. Using random forest regression, we show that mutational distributions in normal cells closely match the epigenetic landscapes of their corresponding cell types. For example, the mutational profile of normal breast tissue maps to the epigenomes of luminal progenitor cells, indicating that these mutations are predominantly acquired during the progenitor cell state. In contrast, mutations observed in ductal carcinoma in situ (DCIS) closely aligns with the epigenomes of mature luminal cells, reflecting a distinct pattern of mutation accumulation in the precancerous state compared to normal tissue. Building on this, we extended our analysis to cancer by comparing normal mutational profiles with data from 2,550 whole genomes spanning 32 cancer types. This reveals both close relationships and distinct origins of different cancer types and subtypes. For example, the different molecular subtypes of breast cancer are associated with specific cell types of the luminal cell lineage, with basal-like subtypes originating from luminal progenitors and all other subtypes (LumA, LumB, Her2) from luminal mature cells. Together, these findings demonstrate that both normal and cancer tissues retain a mutational profile ‘scar’ that reflects the ancestral cell state in which these mutations originally arose. This genomic ‘historical record’ of somatic mutations is a powerful tool for tracing the cellular origins of cancer and provides a framework for understanding how somatic evolution in normal tissues sets the stage for tumor initiation and subtype differentiation. With this approach, we are advancing our understanding of tumorigenesis and subtype differentiation, paving the way for more precise cancer diagnosis and tailored therapeutic strategies.
Citation Format
Kirsten Kübler, Rosa Karlić, Mendy Miller, Chip Stewart, William D. Foulkes, Paz Polak, Peter F. Arndt, Gad Getz. Mutational patterns in normal tissue hold the key to understanding the cellular origins of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6437.
The Marathon of Hope Cancer Centres Network (MOHCCN), led by the Terry Fox Research Institute and the Terry Fox Foundation, unites researchers, clinicians, patients, funders, and other partners across Canada to accelerate precision oncology, promote collaboration and data sharing, and ultimately improve patient outcomes. This overview outlines the Network’s goals, history, and challenges and opportunities. We also highlight progress toward the “MOHCCN Gold Cohort,” a shared resource of clinical and genomic data from 15,000 patients.
Gene genealogies represent the ancestry of a sample and are often encoded as ancestral recombination graphs (ARG). It has recently become possible to infer these gene genealogies from sequencing or genotyping data and use them for evolutionary and statistical genetics. Unfortunately, inferred gene genealogies can be noisy and subject to biases, making their applications more challenging. This project aims to study the application of ARG methods to systematically impute and trace the transmission of all disease variants in founder populations where long-shared haplotypes allow for accurate timing of relatedness. We applied these methods to the population of Quebec, where multiple founder events led to an uneven distribution of pathogenic variants across regions and where extensive population pedigrees are available.
We validated our approach with nine founder mutations for the SLSJ region, demonstrating high accuracy for mutation age, imputation, and regional frequency estimation. Moreover, we showed that this subset of high-quality carriers is sufficient to capture previously described associations with pathogenic variants in the LPL gene. This method systematically characterizes rare variants in founder populations, establishing a fast and accurate approach to inform genetic screening programs.
... We have read with great interest the case report by David Langleben and colleagues, which describes the ineffectiveness of sotatercept in a patient with heritable pulmonary arterial hypertension (HPAH) who carried a missense mutation in the GDF2 gene (BMP9, c.1276 T>C, p. [Cys 426 Arg]) [1]. Although caution is required when drawing general conclusions from findings in a single patient, the reported case study may add novel insights to our understanding of the complex interplay between genetic mutations and targeted therapies in PAH. ...
... All pathogenic and likely pathogenic variants detected by WES were confirmed by Sanger sequencing. Variant classification was performed according to the ACMG guidelines [4]. ...
... This highlights the importance of targeted public health interventions to reduce disparities a greater burden is borne by older generations. As far as prevention is concerned, it would be beneficial to start with the middle-aged population before they enter these high-risk age groups [40]. ...
... Two recently published guidelines recommend annual physical examinations and the commencement of ultrasound surveillance at age 12 years, repeating every 3 years in the absence of nodules. If nodules are detected, ageappropriate guidelines for evaluation and management should be followed [53,54]. ...
... Whilst appropriate for our research question, UK Biobank cohort show healthy recruitment effect as clearly observed in sex specific cancers. 31 This and the minimum recruitment age of 40 years could have depleted the cohort of high/highest risk variants and missed MTC cases who died earlier. However, this potential depletion does not apply to incidentally identified RET variants in over 40 year olds and their follow up data. ...
... No contexto de mulheres portadoras de mutações conferidoras de risco oncológico nos genes BRCA 1 e 2, Phillips K et al., conduziram um estudo observacional, incluindo dados de 4 estudos coorte prospetivos, com o objetivo de avaliar a associação entre a contraceção hormonal e cancro da mama nestas mulheres 6 . Foram incluídas 5.391 mulheres, 3.882 com mutação BRCA1 e 1.509 com BRCA2 com toma em algum momento da sua vida de contraceção hormonal. ...
... Variants that alter canonical splice sites (donor, + 1 and + 2; acceptor, − 1 and − 2) are generally assumed to result in a complete loss of WT transcripts [64][65][66][67]. However, an increasing number of canonical 5′ splice site + 2T > C (GT > GC) variants challenge this assumption, as they continue to produce some WT transcripts [66,[68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83]. ...
... Our study reports findings from a cohort of 912 patients with BC who underwent germline testing for 14 BC and Lynch syndrome-related genes. We detected PVs in 14.1% of patients, a higher rate than typically reported in unselected cohorts, 30 which likely reflects our cohort's selection based on clinical criteria such as family history, early-onset disease, and TNBC. High-risk PVs in genes such as BRCA1, BRCA2, PALB2, and TP53 significantly influence management decisions, including surgical options like RRMs and the use of adjuvant therapies. ...
... 22 The risk of primary peritoneal cancer remains even after undergoing RRSO. According to a recent international, multicenter, and longitudinal study by Narod et al., 25 among 6310 gBRCA1/2 PV carriers who under-went RRSO, the cumulative risk of primary peritoneal cancer over 20 years post-RRSO was 2.7% for gBRCA1 carriers and 0.9% for gBRCA2 carriers. Notably, primary peritoneal cancer did not occur in gBRCA1 carriers who underwent RRSO by age 35 or in gBRCA2 carriers who underwent RRSO by age 45. 25 These findings support the importance of having RRSO performed at the appropriate age. ...
... The resulting Clinical Cancer Research (CCR) pediatric oncology series provides a comprehensive overview and recommendations for surveillance of the 50 most common CPS, each carrying a 5% or greater cancer risk within the first 20 years of life [1,[20][21][22][23][24][25][26][27][28][29][30][31][32][33]. These recommendations were recently updated [34][35][36]. Building upon this fundamental work, the present review aims to provide an organ-specific overview of non-malignant signs and symptoms associated with CPS, offering a practical guide for daily practice (Fig. 1). This detailed exploration includes skin anomalies, neurological and developmental symptoms, growth and metabolic disorders, craniofacial dysmorphisms, ocular signs, head, neck, and thyroid anomalies, abdominal and gastrointestinal manifestations, musculoskeletal anomalies, pulmonary manifestations, cardiovascular signs, genitourinary issues, tumor development in a non-cancerous context, and prenatal deviations. ...
