Germline TTN variants are enriched in PTEN-wildtype Bannayan–Riley–Ruvalcaba syndrome

Abstract

Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare congenital disorder classically characterized by macrocephaly in combination with intestinal hamartomatous polyposis, vascular malformations, lipomas, and genital lentiginosis. Germline PTEN mutations have been reported in up to 60% of BRRS patients. The remaining cases are of unknown genetic etiology. We exome-sequenced 35 unrelated PTEN-wildtype patients with classic presentation of BRRS and identified TTN germline missense variants in 12/35 (34%) patients. TTN encodes TITIN, a key structural and functional muscle protein. Exome and TTN-targeted sequencing in an additional unrelated series of 231 BRRS-like patients revealed 37 (16%) additional patients with germline TTN variants. All variants were predicted to be deleterious and equally distributed between the A-band and I-band protein domains. Rare TTN variants (MAF ≤ 0.0001) are enriched in classic BRRS patients compared to BRRS-like (OR = 2.7, 95% CI 1.21-5.94, p = 1.6 × 10-2) and multiple population controls (OR = 2.2, 95% CI 1.01-4.20, p = 4.7 × 10-2). Germline TTN mutations of different genotypes, inheritance patterns, and protein domain enrichment have been identified in multiple cardiac and/or skeletal muscular disorders. Functional interrogation of I-band variant p.Cys5096Arg identified in one of our classic BRRS patients, using CRISPR-Cas9 genome-edited cell lines, reveals an increased growth and lack of contact inhibition phenotype associated with increased levels of or phosphorylation of focal adhesion kinase (FAK) in mutant cells. These findings suggest that TITIN could play a role in overgrowth-relevant pathways and phenotypes. In summary, our observations suggest TTN as a candidate predisposing gene in classic PTEN-wildtype BRRS patients, perhaps suggesting this syndrome join the growing list of Titinopathies.

Mutant‑allele tumor heterogeneity in malignant glioma effectively predicts neoplastic recurrence

“…The TTN gene encodes the titin protein, which performs nucleic acid- and protein-binding functions, and is involved in dilated cardiomyopathy and cardiac conduction disease (38). A recent study demonstrated that TTN serves a role in overgrowth-associated signaling pathways in PTEN-wildtype Bannayan-Riley-Ruvalcaba syndrome (39). Although, to the best of our knowledge, no studies have yet investigated the association between TTN and tumors, data from the TCGA database revealed that the TTN gene has a high frequency of mutation in a number of tumors, including lung (724 cases), skin (379 cases), uterus (282 cases), stomach (274 cases), colon (264 cases) and breast (291 cases) tumors ().…”

Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations

“…This observation corroborates the complexity of hereditary cancer syndromes, and the likelihood that other non-classic cancer-associated genes may contribute to carcinogenesis in these patients. Indeed, we have recently identified SEC23B and USF3 as candidate cancer susceptibility genes in PTEN -wildtype CS, and TTN in PTEN -wildtype BRRS [ 24 , 32 , 33 ]. Importantly, none of these genes were classically known to be associated with a cancer phenotype, reflecting that patients who remain with missing heritability could harbor germline variants in such non-classic genes.…”

Considerations on Diagnosis and Surveillance Measures of PTEN Hamartoma Tumor Syndrome: Clinical and Genetic Study in a Series of Spanish Patients.

“…(31,32) We did not nd candidate variants in SDH-B, SDH-D, PIK3CA, AKT1, TTN or SEC23B; these genes were suggested in the literature to be involved in CS and BRRS. (11)(12)(13)(14) Several LDD patients do not present PTEN alterations and recently EGFR was proposed as a novel candidate for LDD susceptibility. (33,34) Thus, we also sought for other LDD genes through WES in 4 PTEN-wt patients with this cerebellar tumor.…”

“…Variants in SDH-B, SDH-D, PIK3CA, AKT1, TTN and SEC23B, together with hypermethylation of the KLLN promoter, have been previously reported in certain CS, CS-like and BRRS patients. (11)(12)(13)(14)(15) Here, we describe the clinical and molecular aspects of 145 Spanish patients with a phenotype compatible with PHTS entities, to contribute to the knowledge of this rare disease by de ning its characteristics in a new population and searching for other relevant genes.…”