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Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience.

ABSTRACT: Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients.

SUBMITTER: Sculco M

PROVIDER: S-EPMC9317020 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience.

Sculco Marika M La Vecchia Marta M Aspesi Anna A Clavenna Michela Giulia MG Salvo Michela M Borgonovi Giulia G Pittaro Alessandra A Witel Gianluca G Napoli Francesca F Listì Angela A Grosso Federica F Libener Roberta R Maconi Antonio A Rena Ottavio O Boldorini Renzo R Giachino Daniela D Bironzo Paolo P Maffè Antonella A Alì Greta G Elefanti Lisa L Menin Chiara C Righi Luisella L Tampieri Cristian C Scagliotti Giorgio Vittorio GV Dianzani Caterina C Ferrante Daniela D Migliore Enrica E Magnani Corrado C Mirabelli Dario D Matullo Giuseppe G Dianzani Irma I

Diagnostics (Basel, Switzerland) 20220713 7

Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS ...[more]

PMID: 35885614

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Project description:Background/aimsCombined ACE inhibitor, angiotensin-receptor-blocker, non-dihydropyridine calcium-channel-blocker, and statin therapy (Remission Clinic) reduced proteinuria and halted progression in non-diabetic nephropathies, but their efficacy in Alport syndrome (AS) nephropathy is unknown.MethodsFrom February 2004 to September 2007, we included nine albuminuric AS adults with creatinine clearance >20 ml/min/1.73 m(2) in a single-center, open-label, prospective, off-on-off academic study. After the 1-month wash-out from RAS inhibition (Run-in), patients entered the 4-month, add-on, treatment period with benazepril (10-20 mg/day), valsartan (80-160 mg/day), diltiazem (60-120 mg/day), and fluvastatin (40-80 mg/day) followed by the 1-month wash-out (Recovery). The primary outcome was albuminuria at month 4. After recovery, patients were kept on the Remission Clinic protocol and followed until July 2014 (Extension).ResultsThe median (IQR) albuminuria progressively declined from 657.7 (292.7-1,089.6) μg/min at baseline to 71.4 (21.7-504.9) μg/min at treatment end (p = 0.009) and raised to 404.3 (167.9-446.8) μg/min after recovery. Albumin and IgG fractional clearances significantly (p ≤ 0.005) decreased from 66.9 (53.6-80.8) to 9.4 (4.6-26.0) and from 5.1 (3.0-8.4) to 1.1 (0.6-3.2), and then recovered toward baseline. Blood pressure and lipids significantly decreased on treatment, without changes in inulin-measured GFR or para-aminohippuric-measured RPF. After recovery, one patient refused to enter the extension, one with severe renal insufficiency at baseline reached ESRD, and seven retained normal serum creatinine until the end of the study. At the final visit, three were microalbuminuric and one was normoalbuminuric. Treatment was well tolerated.ConclusionThe Remission Clinic approach safely ameliorated albuminuria, blood pressure, lipids, and glomerular selectivity in AS patients and halted long-term progression in those without renal insufficiency to start with.

Dataset Information

Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience.

Publications

Diagnostics of <i>BAP1</i>-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience.

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