Spectrum of BAP1 mutations identified in diverse cancer lineages


Zoran Gatalica, MD, DSc, Joanne Xiu, PhD, Wangjuh Chen, PhD, Jeffrey Swensen, PhD


Germline mutations in the tumor suppressor gene, BAP1, a deubiquitylase that regulates key cellular pathways, are associated with a recently-described tumor predisposition syndrome characterized by early onset benign melanocytic skin tumors, and a significant risk of cancers that include mesothelioma, cutaneous and uveal melanoma, renal cell carcinoma (RCC) and cholangiocarcinoma. Somatic or germline BAP1 mutations have been associated with an aggressive course and a poor prognosis in RCC and cholangiocarcinoma and may render the cancer cells more sensitive to HDAC inhibitors or Parp inhibitors. We investigated types and frequencies of BAP1 mutations in a large cohort of diverse malignancies and their associations with other molecular/genomic characteristics.


A total of 9782 tumor samples from over 40 cancer types were molecularly profiled at Caris Life Sciences by next generation sequencing (Illumina NextSeq platform and Agilent SureSelect XT panel, 592 genes). Microsatellite instability (MSI) was tested by PCR and fragment analysis (Promega MSI Analysis System).


A pathogenic somatic or germline BAP1 mutation was identified in 20 cancer types, with a total of 129 tumors with mutations found (1.3% prevalence). As expected, BAP1 mutations were frequently seen in uveal melanoma (50% or 24 in 48), malignant pleural mesothelioma (29% or 6 in 21), RCC (8% or 12 in 150), cholangiocarcinoma (6.6% or 13 in 196), and cutaneous melanoma (2.2% or 7 in 319). In addition, pathogenic BAP1 mutations were detected in carcinomas arising in parotid gland (10.3% or 3 in 29), anus (8.3% or 3 in 36), cervix (3.4% or 4 in 117), stomach (3.3%, or 6 in 180), head and neck (1 in 97 or 1%), lung (14 in 1590 or 0.9%), and breast (0.8% or 7 in 887). A mutation was also noted in a meningioma (1 in 43) and a uterine sarcoma (1 in 96). Variants of BAP1 (pathogenic, presumed pathogenic, and variants of unknown significance) were more often seen in MSI-high tumors (compared to MSS) in both colorectal (12/61 vs. 18/1003) and endometrial carcinomas (5 of 69 vs. 5 of 321; both p<0.01). It was not determined whether the BAP1 mutations were somatic or germline in origin.


The study confirmed the presence of pathogenic BAP1 mutations in carcinomas commonly associated with BAP1 germline and somatic mutations. It also identified BAP1 mutations in additional cancer types (parotid gland, anal and cervical carcinomas), as well as its association with MSI-H cancers (colon and endometrium). Evaluation of mutations in non-cancerous tissues is underway to determine if these novel cancer associations are related to germline predisposition.

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