First Report of BAP1-associated Polyposis

Abstract

BAP1 Tumor Predisposition Syndrome (BAP1-TPDS) is caused by germline pathogenic variants in the BAP1 gene and has been associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and other benign cutaneous lesions. Adenomatous colon polyposis has not previously been reported as part of BAP1-TPDS. We report two patients with unexplained adenomatous oligopolyposis and germline BAP1 pathogenic variants. To determine if BAP1 had a role in polypogenesis we performed somatic mutational analysis on multiple polyps from both patients (n=8 total polyps tested). In every polyp tested we found evidence of second BAP1 allele inactivation, including second somatic BAP1 mutations. Further, we did not detect any mutations in the commonly identified adenomatous polyposis pathway drivers, APC, CTNNB1 or other WNT/β-catenin. We did not detect somatic BAP1 mutations in any adenomatous polyp from patients without germline BAP1 pathogenic variants (n=151 patients), highlighting the specificity of somatic BAP1 second hit mutations in BAP1 germline carrier polyps. Our findings strongly support that the polyps in these patients were caused by BAP1, and that adenomatous oligopolyposis is a part of the BAP1-TPDS tumor spectrum. Further work is needed to characterize the penetrance of this new BAP1-associated phenotype.

INTRODUCTION:

The BRCA1-associated protein-1 (BAP1) is a tumor suppressor gene whose functions include cell cycle control, DNA damage repair, and apoptosis (Yu et al., 2014, Zhang et al., 2018). Pathogenic variants (PV) in BAP1 are associated with BAP1 Tumor Predisposition Syndrome (BAP1-TPDS), a relatively recently (2011) described tumor predisposition syndrome with evolving knowledge regarding gene-disease associations (Abdel-Rahman et al., 2011, Testa et al., 2011, Wiesner et al., 2011). BAP1-TPDS is associated with benign cutaneous lesions called BAP1-inactivated melanocytic tumors (BIMT), uveal melanoma, mesothelioma, cutaneous melanoma, and renal cell carcinoma. Other suggested BAP1-TPDS-associated neoplasms include meningioma, basal cell carcinoma, cholangiocarcinoma and hepatic cancers (Abdel-Rahman et al., 2011, de la Fouchardière et al., 2015, Shankar et al., 2017, Huang et al., 2018, Walpole et al., 2018). It is well established that genes associated with dysregulation of WNT signaling (e.g. APC, CTNNB1 [protein: β-catenin]) are the most frequently identified drivers in early colorectal adenomas (Wolff et al., 2018, dos Santos et al., 2022). To date, colorectal cancer and adenomatous oligopolyposis (10–99 polyps with adenomatous histology) are not previously reported phenotypes in patients with BAP1-TPDS (Walpole et al., 2018), and it seems to be rare based on clinical experience and registries. Here we report on two patients with germline BAP1 PV and unexplained adenomatous oligopolyposis.

CASE REPORT:

Patient 1 (male) presented at age 64 with at least 29 histologically-proven adenomatous polyps throughout the gastrointestinal tract (gastric, small bowel and large intestine). He was found to have a germline PV in BAP1 designated as NM_004656.4(BAP1):c.1934del (p.Asn645Thrfs*10) via a comprehensive 52-gene next generation sequencing (NGS) panel (BROCA Cancer Risk Panel, University of Washington [Shirts et al., 2016]). The BROCA panel capture includes the coding and select intronic regions of APC, as well as the 5’ untranslated region and promoter 1B, and no APC variants were detected. At the time of polyp testing, no BAP1-related tumors were reported for the patient or in close relatives; however, he was subsequently diagnosed with cholangiocarcinoma and clear cell renal cell carcinoma (Supplemental Figure 1). Family members were not known to have had a colonoscopy nor colon polyps and were not available for BAP1 testing. We tested 6 separate biopsies of polyp samples obtained throughout the gastrointestinal tract (duodenum, stomach, and cecum) and found all 6 to have either a second somatic mutation in BAP1 or loss of the wild type allele (loss of heterozygosity, LOH) (Table 1). We did not identify mutations in APC or other WNT pathway drivers. One cecal and two duodenal polyps shared a BAP1 NM_4656.4(BAP1):c.518A>G (p.Tyr173Cys) mutation, raising the possibility of a hotspot mutation, focal mosaicism / field effect in these three lesions, or less likely metastatic lesions. BAP1 p.Tyr173Cys is a well-known pathogenic variant and relatively common recurring BAP1 mutation (cBioPortal, 10 March 2025). As expected, we also observed BAP1 second allele inactivation in the kidney and liver tumors (Table 1).

Table 1.

Neoplastic Tissue Analyses in Patient 1

Sample Type	Diagnosis	Germline BAP1 Variant1 (VAF)	Somatic BAP1 Mutation (VAF)	Neoplastic Content5	Interpretation
Blood	Peripheral blood	46%	N/A	N/A	Heterozygous
Gastric polyp	Low-grade glandular dysplasia	42%	p.Ile72fs2 (23%)	40%	Biallelic BAP1 loss – germline PV and somatic mutation
Duodenum polyp	Villous adenoma	51%	p.Tyr173Cys3 (26%)	50%	Biallelic BAP1 loss – germline PV and somatic mutation
Duodenum bulb polyp	Low grade glandular dysplasia/adenomatous change	43%	p.Tyr173Cys3 (30%)	60%	Biallelic BAP1 loss – germline PV and somatic mutation
Duodenal bulb polyp	Low grade glandular dysplasia/adenomatous changes	76%	LOH4	75%	Biallelic BAP1 loss – germline PV with LOH
Cecum polyp	Tubular adenoma	78%	LOH4	70%	Biallelic BAP1 loss – germline PV with LOH
Cecum polyp	Tubular adenoma	45%	p.Tyr173Cys3 (21%)	40%	Biallelic BAP1 loss – germline PV and somatic mutation
Right Kidney tumor	Adenocarcinoma	68%	LOH4	70%	Biallelic BAP1 loss – germline PV with LOH
Liver tumor	Cholangiocarcinoma	55%	LOH4	35%	Biallelic BAP1 loss – germline PV with LOH

¹Germline BAP1 variant in Patient 1 is NM_004656.4(BAP1):c.1934del (p.Asn645Thrfs*10),

²NM_004656.4(BAP1):c.216del (p.Ile72Metfs*6),

³NM_4656.4(BAP1):c.518A>G (p.Tyr173Cys).

⁴The ColoSeq Polyposis assay assesses LOH with both a clinically-validated b-allele single nucleotide polymorphism (SNP) caller and the variant allele fraction(s) in the context of tumor fraction and difference in VAF from the known variant allele fraction on this specific assay for the germline call; see Supplemental Table 1 for the approximate size and genomic breakpoints of LOH events.

⁵Neoplastic content is estimated by histological review of hematoxylin and eosin-stained slides by a trained molecular pathologist and two in silico algorithms which account for mutation fractions and b allele SNPs.

Patient 2 is a 49-year-old male with 14 adenomatous colon polyps identified on his index screening colonoscopy. A 71-gene hereditary cancer multi-gene panel (CancerNext Expanded+RNAnalysis, Ambry Genetics) was performed based on his polyposis history with the only finding being a pathogenic germline variant in BAP1 NM_004656.4(BAP1):c.293del (p.Ser98Thrfs*4). The patient’s history is significant for a skin cancer diagnosis (pathology uncertain) at 47 years of age. The family history for this patient is largely unknown with the only significant family history reported being ovarian cancer in his mother which was diagnosed in her early 60s (Supplemental Figure 2), and no family members were tested for the BAP1 variant, and their colonoscopy status was unknown. Given the unexplained polyposis and questions pertaining to the possibility of BAP1 playing a role, we evaluated the germline and two of the patient’s polyps via a somatic panel (ColoSeq^™ Polyposis, University of Washington) to assess for APC mosaicism or other genomic causes. ColoSeq Polyposis and CancerNext panel captures include APC promoter 1B and ColoSeq Polyposis includes the 5’ untranslated region of APC. We identified a somatic second hit BAP1 mutation in the first polyp and loss of the inherited BAP1 allele (loss of heterozygosity) in the second polyp (Table 2). No PVs were identified in APC or other WNT pathway drivers.

Table 2.

Neoplastic Tissue Analyses in Patient 2

Sample Type	Diagnosis	Germline BAP1 Variant1 (VAF)	Somatic BAP1 mutation (VAF)	Neoplastic Content3	Interpretation
Saliva	Saliva	46%	N/A	N/A	Heterozygous
Ascending / hepatic flexure colon polyp	Tubular adenoma	68%	p.Glu454fs2 (7%) and LOH4	70%	Biallelic BAP1 loss – germline PV and somatic mutation
Transverse colon polyp	Tubular adenoma	84%	LOH4	85%	Biallelic BAP1 loss – germline PV with LOH

¹Germline BAP1 variant in Patient 2 is NM_004656.4(BAP1):c.293del (p.Ser98Thrfs*4),

²NM_004656.4(BAP1):c.1359dup (p.Glu454Argfs*15).

³Neoplastic content is estimated by histological review of hematoxylin and eosin-stained slides by a trained molecular pathologist and two in silico algorithms which account for mutation fractions and b allele SNPs.

⁴The ColoSeq Polyposis assay assesses LOH with both a clinically-validated b-allele single nucleotide polymorphism (SNP) caller and the variant allele fraction(s) in the context of tumor fraction and difference in VAF from the known variant allele fraction on this specific assay for the germline call; see Supplemental Table 2 for the approximate size and genomic breakpoints of LOH events.

To determine the specificity of identifying somatic BAP1 inactivating mutations in adenomatous polyps we reviewed polyp sequencing data from 151 polyposis patients without germline BAP1 PV who underwent ColoSeq Polyposis testing and did not identify any somatic BAP1 mutations.

DISCUSSION:

We report two individuals with strong molecular evidence pointing toward BAP1-driven adenomatous oligopolyposis. While we recognize that data from only 2 patients is insufficient for formulating guidelines, the findings suggest the possible need for increased endoscopic surveillance in patients with BAP1-TPDS, and the consideration for BAP1 to be added to polyposis focused multi-gene hereditary cancer panels. To better understand the significance of these findings, we encourage those who see BAP1-TPDS patients clinically, or in a research setting, to consider comprehensive review of endoscopic (colonoscopy and esophagogastroduodenoscopy) records. Participation in BAP1-TPDS registries with collection of colorectal cancer and gastrointestinal polyp data will be vital to better understand this possible association. Because colorectal cancer is not common in patients with BAP1 pathogenic variants, it is not clear that the earlier or more frequent endoscopic surveillance would impact colorectal cancer risk. These two patients’ histories suggest that adenomatous polyps are not developing at an early age and evaluation of the natural history of BAP1-driven polyposis in a larger cohort is needed to better understand the polyp burden and onset. Lastly, given the lack of variants in genes associated with WNT signal dysregulation our data suggests that BAP1 may contribute to colon neoplastic proliferation via another mechanism. Continued research on this topic is warranted.

CONSENT:

Both Patient #1 and Patient #2 agreed to participation in their case report and signed a permission to release protected health information for publication and educational purposes.