Rare disease gene association discovery in the 100,000 Genomes Project.

Up to 80% of rare disease patients remain undiagnosed after genomic sequencing, with many probably involving pathogenic variants in yet to be discovered disease-gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project. A total of 141 new associations were identified, including five for which independent disease-gene evidence was recently published.

Metastatic malignant cylindroma arising on a background of digenic inheritance of BRCA2 and CYLD pathogenic variants targeted with PARP inhibition.

Background: CYLD cutaneous syndrome (CCS) is caused by germline heterozygous pathogenic variants in CYLD and results in progressive formation of cylindromas, spiradenomas, or trichoepitheliomas. Malignant cylindroma is a rare skin adnexal tumour occurring in CCS that can metastasize with lethal outcomes and has limited genomic characterization. BRCA2 loss in CCS is not described and may modulate the cutaneous cancer risk of CCS.

A novel microsatellite instability test of sebaceous tumours to facilitate low cost universal screening for Lynch syndrome.

Background: One in five sebaceous tumour (ST) patients may have Lynch syndrome (LS), a hereditary cancer predisposition. LS patients benefit from cancer surveillance and prevention programmes and immunotherapy. Whilst universal tumour mismatch repair (MMR) deficiency testing is recommended in colorectal and endometrial cancers to screen for LS, there is no consensus screening strategy for ST, leading to low testing rates and inequity of care.

Exploration of the mutational landscape of cutaneous leiomyoma confirms FH as a driver gene and identifies targeting purine metabolism as a potential therapeutic strategy.

To comprehensively explore the mutational landscape of cutaneous leiomyoma (cLM) and identify candidate driver events, we performed a retrospective, multi-institutional, whole-exome sequencing and RNA sequencing study. We confirmed that a large proportion of patients with cLM have germline variants and additionally showed that somatic alteration of also drives cLM, with biallelic inactivation of being a frequent event. Treatment of -proficient and -deficient cell lines with the purine antagonist and chemotherapeutic agent, mercaptopurine, significantly decreased growth/colony formation; however, the addition of nucleosides was able to rescue only the -proficient cells, suggesting that purine metabolism is a targetable vulnerability for -deficient cLMs.

Monitoring immunE DysregulAtion foLLowing Immune checkpOint-inhibitioN (MEDALLION): protocol for an observational cancer immunotherapy cohort study.

Background: Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden.

National epidemiology of digital papillary adenocarcinoma in England 2013-2020: a population-based registry study.

Background: Digital papillary adenocarcinoma (DPA), formerly known as aggressive DPA, is a rare adnexal cancer of sweat gland differentiation with metastatic potential. DPA epidemiology and patient outcome data are prerequisites for developing diagnostic and therapeutic guidance, which are lacking for this rare cancer.

Objectives: To report the incidence, patient demographics and treatment of patients with DPA in England from 1 January 2013 to 31 December 2020 using national cancer registry data.

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with , and independent confirmatory evidence has recently been published for four more.

Clinical Outcomes in Sebaceous Carcinoma: A Retrospective Two-Center Cohort Study.

Background: Sebaceous carcinoma (SC) is a rare, potentially recurrent, and life-threatening cutaneous malignancy that can be associated with Muir-Torre syndrome (MTS), a DNA mismatch repair-driven genodermatosis. Earlier studies examining factors associated with recurrence have focused on periocular tumors only.

Objective: Examine outcomes of SC and identify factors associated with recurrence.