The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research

Abstract

Despite collectively accounting for 25% of tumors in U.S. adults, rare cancers have significant unmet clinical needs as they are difficult to study due to low incidence and geographically dispersed patient populations. We sought to assess whether a patientpartnered research approach using online engagement can overcome these challenges and accelerate scientific discovery in rare cancers, focusing on angiosarcoma (AS), an exceedingly rare sarcoma with a dismal prognosis and an annual U.S. incidence of 300 cases. Here, we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling patients across the U.S. and Canada to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 AS patients registered for the ASCproject, comprising a significant fraction of all patients. Whole exome sequencing of 47 AS tumors revealed several recurrently mutated genes, including KDR, TP53, and PIK3CA. Activating mutations in PIK3CA were observed nearly exclusively in primary breast AS, suggesting a therapeutic rationale in these patients. AS of the head, neck, face, and scalp (HNFS) was associated with high tumor mutation burden and a dominant mutational signature of UV light exposure, suggesting that UV damage may be a causative factor in HNFS AS and that this AS subset might be amenable to immune checkpoint inhibitor therapy. Medical record review revealed two patients with HNFS AS received off-label treatment with anti-PD-1 therapy and experienced exceptional responses, highlighting immune checkpoint inhibition as a therapeutic avenue for HNFS AS. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for AS patients. Collectively, this proof of concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and enable biological and clinical discoveries.

POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families

“…These POT1 mutations were distributed across all conserved domains. Our analyses of angiosarcoma tumour genomes revealed a high frequency of POT1 mutations distributed in a similar pattern, complementing other emerging studies that have observed a high frequency of POT1 mutations in angiosarcoma 33. Because the database lacks family history data, the cases profiled in the current study may contain patients meeting criteria for LFLS.…”

Canine tumor mutation rate is positively correlated with TP53 mutation across cancer types and breeds

“…We noted that each canine cancer type shares major pathway alterations with its human counterpart ( Figure 2), including breast cancer, pediatric and adult glioma, diffuse large B-cell lymphoma, oral melanoma, osteosarcoma, or angiosarcoma 3,4,[24][25][26][27] . In both species, p53 pathway alteration and cell cycle alteration are common in osteosarcoma and oral melanoma ( Figures 2D and 2E).…”

“…Mutated genes and altered pathways in human cancers were extracted from published studies, including 996 breast cancers 24,25 , 91 high grade pediatric gliomas 40,41 , 507 adult low grade gliomas 12 , 48 diffuse large B-cell lymphomas 25 , 65 oral melanomas 27 , 58 pediatric osteosarcomas 3,4 , and 48 angiosarcomas 26 .…”

“…Finally, Fisher's test was applied to test differences in the ratio of DNA-repair variants between two breeds using the DNA-repair and non-DNA-repair variant counts in the two breeds. are from published studies 3,4,[24][25][26][27] . See also Figure S2 and Table S1B.…”

“…We used 601 cases with WES data [11][12][13][15][16][17] for discovery, and 18 with WES data 18,23 and 91 with WGS data [18][19][20][21][22] for validation. We also compared our canine findings to those published for the corresponding human cancers 3,4,[24][25][26][27] . The study is described below.…”