ALK-rearranged renal cell carcinoma (ALK-RCC) is rare, molecularly defined RCC subtype in the recently published fifth edition of World Health Organization classification of tumors. In this study, we described 9 ALK-RCCs from a clinicopathologic, immunohistochemical, and molecular genetic aspect, supporting and extending upon the observations by previous studies regarding this rare subgroup of RCC. There were 6 male and 3 female patients with ages ranging from 14 to 59 years (mean, 34.4 years). None of the patients had sickle cell trait. The diagnosis was based on radical or partial nephrectomy specimen for 8 patients and on biopsy specimen for 1. Tumor size ranged from 2.5 to 7.2 cm (mean, 2.8 cm). Follow-up was available for 6 of 9 patients (6-36 months); 5 had no tumor recurrence or metastasis and 1 developed lung metastasis at 24 months. The patient was subsequently treated with resection of the metastatic tumor followed by crizotinib-targeted therapy, and he was alive without tumor 12 months later. Histologically, the tumors showed a mixed growth of multiple patterns, including papillary, solid, tubular, tubulocystic, cribriform, and corded, often set in a mucinous background. The neoplastic cells had predominantly eosinophilic cytoplasm. Focally, clear cytoplasm with polarized nuclei and subnuclear vacuoles (n = 1), and pale foamy cytoplasm (n = 1) were observed on the tumor cells. The biopsied tumor showed solid growth of elongated tubules merging with bland spindle cells. Other common and uncommon features included psammomatous microcalcifications (n = 5), rhabdoid cells (n = 4), prominent intracytoplasmic vacuoles (n = 4), prominent chronic inflammatory infiltrate (n = 3), signet ring cell morphology (n = 2), and pleomorphic cells (n = 2). By immunohistochemistry, all 9 tumors were diffusely positive for ALK(5A4) and 4 of 8 tested cases showed reactivity for TFE3 protein. By fluorescence in situ hybridization analysis, ALK rearrangement was identified in all the 9 tumors; none of the tested tumors harbored TFE3 rearrangement (0/4) or gains of chromosomes 7 and 17 (0/3). ALK fusion partners were identified by RNA-sequencing in all 8 cases analyzed, including EML4 (n = 2), STRN (n = 1), TPM3 (n = 1), KIF5B (n = 1), HOOK1 (n = 1), SLIT1 (n = 1), and TPM1(3\' UTR) (n = 1). Our study further expands the morphologic and molecular genetic spectrum of ALK-RCC.

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder characterized by marked clinical and genetic heterogeneity. Ethnic groups underrepresented in studies may have distinctive characteristics. We sought to evaluate the clinical and genetic landscape of Russian HCM patients. A total of 193 patients (52% male; 95% Eastern Slavic origin; median age 56 years) were clinically evaluated, including genetic testing, and prospectively followed to document outcomes. As a result, 48% had obstructive HCM, 25% had HCM in family, 21% were asymptomatic, and 68% had comorbidities. During 2.8 years of follow-up, the all-cause mortality rate was 2.86%/year. A total of 5.7% received an implantable cardioverter-defibrillator (ICD), and 21% had septal reduction therapy. A sequencing analysis of 176 probands identified 64 causative variants in 66 patients (38%); recurrent variants were MYBPC3 p.Q1233* (8), MYBPC3 p.R346H (2), MYH7 p.A729P (2), TPM1 p.Q210R (3), and FLNC p.H1834Y (2); 10 were multiple variant carriers (5.7%); 5 had non-sarcomeric HCM, ALPK3, TRIM63, and FLNC. Thin filament variant carriers had a worse prognosis for heart failure (HR = 7.9, p = 0.007). In conclusion, in the Russian HCM population, the low use of ICD and relatively high mortality should be noted by clinicians; some distinct recurrent variants are suspected to have a founder effect; and family studies on some rare variants enriched worldwide knowledge in HCM.

OBJECTIVE: TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees.
METHODS: TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain.
RESULTS: The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect.
CONCLUSIONS: TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.