Germline Variation Controls the Architecture of Somatic Alterations in Tumors

Studies have suggested that somatic events in tumors can depend on an individual's constitutional genotype. We used squamous cell carcinomas (SCC) of the skin, which arise in high multiplicity in organ transplant recipients, as a model to compare the pattern of somatic alterations within and across individuals. Specifically, we performed array comparative genomic hybridization on 104 tumors from 25 unrelated individuals who each had three or more independently arisen SCCs and compared the profiles occurring within patients to profiles of tumors across a larger set of 135 patients. In general, chromosomal aberrations in SCCs were more similar within than across individuals (two-sided exact-test p-value ), consistent with the notion that the genetic background was affecting the pattern of somatic changes. To further test this possibility, we performed allele-specific imbalance studies using microsatellite markers mapping to 14 frequently aberrant regions of multiple independent tumors from 65 patients. We identified nine loci which show evidence of preferential allelic imbalance. One of these loci, 8q24, corresponded to a region in which multiple single nucleotide polymorphisms have been associated with increased cancer risk in genome-wide association studies (GWAS). We tested three implicated variants and identified one, rs13281615, with evidence of allele-specific imbalance (p-value = 0.012). The finding of an independently identified cancer susceptibility allele with allele-specific imbalance in a genomic region affected by recurrent DNA copy number changes suggest that it may also harbor risk alleles for SCC. Together these data provide strong evidence that the genetic background is a key driver of somatic events in cancer, opening an opportunity to expand this approach to identify cancer risk alleles

PTK (protein tyrosine kinase)-6 and HER2 and 4, but not HER1 and 3 predict long-term survival in breast carcinomas

The HER receptors are of therapeutic and prognostic significance in breast cancer, and their function is modulated by cytoplasmic tyrosine kinases like PTK6 (brk). We performed a retrospective study on archival breast cancer samples from patients with long follow-up and compared the protein expression between individual HERs and between HERs and the PTK6. Univariate and multivariate analyses were used to study the prognostic value of parameters. Metastases-free survival of patients for longer than 240 months was inversely associated (P⩽0.05) with nodal status, tumour size, and oestrogen receptor status, but was also directly associated with high protein expression levels of HER4 and PTK6 in Kaplan–Meier analysis. In multivariate analysis for metastases-free survival of >240 months, the stepwise selected parameters were tumour size (relative risk 3.1), PTK6 expression (0.4), and number of positive lymph nodes (1.2). Furthermore, we demonstrated a timedependence of the prognostic value attributed to the parameters. The HER receptors (HER2,4), but not PTK6, were independent prognostic markers for metastases-free survival at 60 months, whereas at 240 months PTK6 is the strongest prognostic marker. We demonstrate that PTK6 is a prognostic marker of metastases-free survival in breast cancer, and is independent of the classical morphological and molecular markers of lymph node involvement, tumour size, and HER2 status

Nevoid basal cell carcinoma syndrome (Gorlin syndrome)

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a hereditary condition characterized by a wide range of developmental abnormalities and a predisposition to neoplasms

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment

A mutation in the V1 end domain of keratin 1 in non-epidermolytic palmar-plantar keratoderma.

Mutations in keratin 9 have been found in families with an epidermolytic form of palmar-plantar keratoderma (PPK). In another form of PPK (Unna-Thost type), epidermolysis is not observed histologically. We studied a pedigree with this non-epidermolytic form of PPK. By gene linkage analysis, the type I keratin locus could be excluded but complete linkage with the type II keratin region was found. Sequence analysis identified a single base change in the amino-terminal V1 variable subdomain of keratin 1, which caused a lysine to isoleucine substitution. This non-conservative mutation completely cosegregated with the disease and was not observed in 50 unrelated unaffected individuals. An examination of keratin amino-terminal sequences revealed a previously unreported 22-residue window in the V1 subdomain that is conserved among most type II keratins. The altered lysine is an invariant residue in this conserved sequence. Previously described keratin mutations affect the central regions important for filament assembly and stability, and cause diseases characterized by cellular degeneration or disruption. This is the first disease mutation in a keratin chain variable end region. The observation that it is not associated with epidermolysis supports the concept that the amino-terminal domain of keratins may be involved in supramolecular interactions of keratin filaments rather than stability. Therefore, hyperkeratosis associated with this mutation may be due to perturbations in the interactions of the keratin end domain with other cellular components

A mutation in the V1 end domain of keratin 1 in non-epidermolytic palmar-plantar keratoderma.

Mutations in keratin 9 have been found in families with an epidermolytic form of palmar-plantar keratoderma (PPK). In another form of PPK (Unna-Thost type), epidermolysis is not observed histologically. We studied a pedigree with this non-epidermolytic form of PPK. By gene linkage analysis, the type I keratin locus could be excluded but complete linkage with the type II keratin region was found. Sequence analysis identified a single base change in the amino-terminal V1 variable subdomain of keratin 1, which caused a lysine to isoleucine substitution. This non-conservative mutation completely cosegregated with the disease and was not observed in 50 unrelated unaffected individuals. An examination of keratin amino-terminal sequences revealed a previously unreported 22-residue window in the V1 subdomain that is conserved among most type II keratins. The altered lysine is an invariant residue in this conserved sequence. Previously described keratin mutations affect the central regions important for filament assembly and stability, and cause diseases characterized by cellular degeneration or disruption. This is the first disease mutation in a keratin chain variable end region. The observation that it is not associated with epidermolysis supports the concept that the amino-terminal domain of keratins may be involved in supramolecular interactions of keratin filaments rather than stability. Therefore, hyperkeratosis associated with this mutation may be due to perturbations in the interactions of the keratin end domain with other cellular components

Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome

Nevoid basal cell carcinoma syndrome (NBCC; Gorlin syndrome), an autosomal dominant disorder linked to 9q22.3-q31, and caused by mutations in PTC, the human homologue of the Drosophila patched gene, comprises multiple basal cell carcinomas, keratocysts of the jaw, palmar/plantar pits, spine and rib anomalies and calcification of the falx cerebri. We reviewed the findings on 105 affected individuals examined at the NIH since 1985. The data included 48 males and 57 females ranging in age from 4 months to 87 years. Eighty percent of whites (71/90) and 38% (5/13) of African-Americans had at least one basal cell carcinoma (BCC), with the first tumor occurring at a mean age of 23 (median 20) years and 21 (median 20) years, respectively. Excluding individuals exposed to radiation therapy, the number of BCCs ranged from 1 to &gt; 1,000 (median 8) and 1 to 3 (median 2), respectively, in the 2 groups. Jaw cysts occurred in 78/105 (74%) with the first tumor occurring in 80% by the age of 20 years. The number of total jaw cysts ranged from 1 to 28 (median 3). Palmar pits and plantar pits were seen in 87%. Ovarian fibromas were diagnosed by ultrasound in 9/52 (17%) at a mean age of 30 years. Medulloblastoma occurred in 4 patients at a mean age of 2.3 years. Three patients had cleft lip or palate. Physical findings include "coarse face" in 54%, relative macrocephaly in 50%, hypertelorism in 42%, frontal bossing in 27%, pectus deformity in 13%, and Sprengel deformity in 11%. Important radiological signs included calcification of the falx cerebri in 65%, of the tentorium cerebelli in 20%, bridged sella in 68%, bifid ribs in 26%, hemivertebrae in 15%, fusion of the vertebral bodies in 10%, and flame shaped lucencies of the phalanges, metacarpal, and carpal bones of the hands in 30%. Several traits previously considered components of the syndrome (including short fourth metacarpal, scoliosis, cervical ribs and spina bifida occulta) were not found to be significantly increased in the affected individuals. This study delineates the frequency of the clinical and radiological anomalies in NBCC in a large population of US patients and discusses guidelines for diagnosis and management