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Boris C Bastian

Publications and source records attributed to Boris C Bastian.

At least 19 recordsLinked to original sources
PubMed2006

In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling.

Melanocytes require the RAS/RAF/MEK/ERK and the cyclic AMP (cAMP) signaling pathways to maintain the fine balance between proliferation and differentiation. We have investigated how cross-talk between these pathways affects melanoma progression. We show that cAMP suppresses CRAF activity in melanocytes and that this is essential to suppress the oncogenic potential of CRAF in these cells. As a consequence, BRAF alone is responsible for signaling to MEK. However, when RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF. This switch is accompanied by dysregulated cAMP signaling, a step that is necessary to allow CRAF to signal to MEK. Thus, a fundamental switch in RAF isoform usage occurs when RAS is mutated in melanoma, and this occurs in the context of disrupted cAMP signaling. These data have important implications for the development of therapeutic strategies to treat this life-threatening disease.

Animals↗
PubMed2006

Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway.

Dysfunction of the endoplasmic reticulum (ER) has been reported in a variety of human pathologies, including cancer. However, the contribution of the ER to the early stages of normal cell transformation is largely unknown. Using primary human melanocytes and biopsies of human naevi (moles), we show that the extent of ER stress induced by cellular oncogenes may define the mechanism of activation of premature senescence. Specifically, we found that oncogenic forms of HRAS (HRAS(G12V)) but not its downstream target BRAF (BRAF(V600E)), engaged a rapid cell-cycle arrest that was associated with massive vacuolization and expansion of the ER. However, neither p53, p16(INK4a) nor classical senescence markers--such as foci of heterochromatin or DNA damage--were able to account for the specific response of melanocytes to HRAS(G12V). Instead, HRAS(G12V)-driven senescence was mediated by the ER-associated unfolded protein response (UPR). The impact of HRAS on the UPR was selective, as it was poorly induced by activated NRAS (more frequently mutated in melanoma than HRAS). These results argue against premature senescence as a converging mechanism of response to activating oncogenes and support a direct role of the ER as a gatekeeper of tumour control.

Cell Cycle↗
PubMed2006

Somatic activation of KIT in distinct subtypes of melanoma.

PURPOSE: Melanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogen-activated protein (MAP) kinase pathway commonly mutated in melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS. PATIENTS AND METHODS: We analyzed array comparative genomic hybridization data from 102 primary melanomas (38 from mucosa, 28 from acral skin, and 18 from skin with and 18 from skin without chronic sun-induced damage) for DNA copy number aberrations specific to melanoma subtypes where mutations in BRAF and NRAS are infrequent. A narrow amplification on 4q12 was found, and candidate genes within it were analyzed. RESULTS: Oncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary melanomas found mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels. CONCLUSION: KIT is an important oncogene in melanoma. Because the majority of the KIT mutations we found in melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global melanoma burden.

Adult↗
PubMed2006

Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations.

Most melanocytic nevi develop on sun-exposed skin during childhood and adolescence and commonly harbor BRAF mutations or, less frequently, NRAS mutations. A small subset of nevi is present at birth, and therefore must develop independently of UV light. To assess whether these nevi have a different mutation spectrum than those that develop on sun-exposed skin, we determined the BRAF and NRAS mutation frequencies in 32 truly congenital nevi. We found no BRAF mutations, but 81% (26/32) harbored mutations in NRAS. Consistently, seven of 10 (70%) proliferating nodules that developed early in life in congenital nevi showed mutations in NRAS. A separate set of nevi that displayed histological features frequently found in nevi present at birth ("congenital pattern nevi") but lacked a definitive history of presence at birth showed an inverse mutation pattern with common BRAF mutations (20/28 or 71%) and less frequent NRAS mutations (7/28 or 25%). Thus, nevi that develop in utero are genetically distinct from those that develop later, and histopathologic criteria alone are unable to reliably distinguish the two groups. The results are consistent with the finding in melanoma that BRAF mutations are uncommon in neoplasms that develop in the absence of sun-exposure.

Adolescent↗
PubMed2006

MC1R germline variants confer risk for BRAF-mutant melanoma.

Germline variants in MC1R, the gene encoding the melanocortin-1 receptor, and sun exposure increase risk for melanoma in Caucasians. The majority of melanomas that occur on skin with little evidence of chronic sun-induced damage (non-CSD melanoma) have mutations in the BRAF oncogene, whereas in melanomas on skin with marked CSD (CSD melanoma) these mutations are less frequent. In two independent Caucasian populations, we show that MC1R variants are strongly associated with BRAF mutations in non-CSD melanomas. In this tumor subtype, the risk for melanoma associated with MC1R is due to an increase in risk of developing melanomas with BRAF mutations.

Adolescent↗
PubMed2005

Distinct sets of genetic alterations in melanoma.

BACKGROUND: Exposure to ultraviolet light is a major causative factor in melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of melanoma with different susceptibility to ultraviolet light. METHODS: We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas. RESULTS: We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of genomic DNA. In two-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84 percent accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89 percent accuracy. Eighty-one percent of melanomas on skin without chronic sun-induced damage had mutations in BRAF or N-RAS; the majority of melanomas in the other groups had mutations in neither gene. Melanomas with wild-type BRAF or N-RAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1), downstream components of the RAS-BRAF pathway. CONCLUSIONS: The genetic alterations identified in melanomas at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or N-RAS.

Adult↗
PubMed2005

Genomic analysis of blue nevi and related dermal melanocytic proliferations.

Blue nevi are benign dermal melanocytic proliferations that can sometimes share overlapping microscopic features with melanoma. We used comparative genomic hybridization to analyze three groups of dermal melanocytic proliferations. Group 1 consisted of 10 cellular blue nevi and 1 deep penetrating nevus, none of which showed chromosomal aberrations. Group 2 consisted of 11 lesions that were histopathologically ambiguous. Three of these lesions demonstrated chromosomal aberrations (three or fewer per lesion). Group 3 consisted of seven histopathologically malignant lesions, each showing three or more chromosomal aberrations. Moderate to severe cytologic atypia and a mitotic rate of three or more mitoses per 10 high power fields were present in six of eight (75%) lesions that had at least three chromosomal aberrations but were absent in 15 of 20 (75%) lesions without chromosomal aberrations. Necrosis was present in four of the 29 (13%) lesions, with every lesion with necrosis demonstrating three or more genomic abnormalities. In conclusion, histopathologically unequivocally benign or malignant dermal melanocytic proliferations show nonoverlapping patterns of chromosomal aberrations. Ambiguous lesions can be separated into lesions with and without chromosomal aberrations. Future studies with clinical follow-up are necessary to determine which aberrations are most informative for classification of these lesions.

Adolescent↗
PubMed2004

Mechanisms of cell-cycle arrest in Spitz nevi with constitutive activation of the MAP-kinase pathway.

Spitz nevi are benign melanocytic nevi that overlap histopathologically with melanoma. We previously found copy number increases of chromosome 11p frequently paralleled by mutations in the HRAS oncogene mapping to this region. In this study, we explored mechanisms that inhibit proliferation in the presence of HRAS activation. We analyzed MAP-kinase activation using immunohistochemistry for phospho-ERK, cyclin D1, and microphthalmia transcription factor expression in 17 Spitz nevi with and 18 Spitz nevi without 11p copy number increase. We found relatively high levels of phospho-ERK and cyclin D1 expression suggesting MAP-kinase pathway activation in both groups of Spitz nevi. However, Spitz nevi with 11p copy number increases showed significantly higher levels of cyclin D1 expression and lower levels of microphthalmia transcription factor expression suggesting stronger MAP-kinase pathway activation in this group. Contrasting this apparent activation, the proliferation rate as assessed by Mib1 expression was low in both groups. An analysis of cell-cycle inhibitory proteins including p16, p21, and p27 showed that the majority of Spitz nevus cells expressed high levels of p16, with cells of the cases that had increased copy number of 11p expressing significantly higher levels than those of Spitz nevi with normal copy number of 11p. We propose that in benign nevi with constitutive activation of the MAP-kinase pathway, p16 functions as an essential mediator of oncogene-induced senescence preventing progression to melanoma.

Calibration↗
PubMed2004

Molecular genetics of melanocytic neoplasia: practical applications for diagnosis.

Pathology is the gold standard for the diagnosis of skin cancer. However, despite morphological criteria that have been constantly refined, there remain areas in which histopathological analysis does not permit an unequivocal diagnosis. Among these, problems most frequently arise with melanocytic lesions. This article reviews recent molecular studies that have revealed differences in the pattern of chromosomal aberrations between naevi and melanoma that could become relevant as adjunctive diagnostic methods in the future.

Chromosome Aberrations↗
PubMed2004

Consumption of the epidermis: a diagnostic criterion for the differential diagnosis of melanoma and Spitz nevus.

The distinction between melanoma and its most important simulant, Spitz nevus, is usually made on microscopically. We point out "consumption of the epidermis" (COE) as an additional diagnostic criterion. We defined COE as thinning of the epidermis with attenuation of the basal and suprabasal layers and loss of rete ridges in areas of direct contact with neoplastic melanocytes. We analyzed 102 unequivocal melanomas and 125 unequivocal Spitz nevi for the presence of COE. COE had not been used in arriving at the diagnosis of these cases because we were unaware of the criterion at the time that the cases were first evaluated. COE was found in 88 of 102 (86%) of melanomas but only 12 of 125 (9.6%) of Spitz nevi (P < 0.001). We then looked for COE in an independent set of 61 ambiguous melanocytic lesions with overlapping histopathologic features that could not be classified unequivocally as Spitz nevus or melanoma. The cases were analyzed by comparative genomic hybridization (CGH) for aberration patterns suggesting a benign or a malignant process, based on previous studies. COE was found in only 6 of 42 (14%) of the ambiguous cases in which CGH suggested a benign process and 14 of 19 (74%) of the ambiguous cases in which CGH suggested melanoma (P < 0.001). Our data suggest that COE is a useful criterion in the evaluation of melanocytic neoplasms. Because COE was frequently found at the edges of ulcers in the majority of ulcerated melanomas, the thinning of the epidermis in COE may represent an early phase of ulceration. This may prove to be important in distinguishing ulceration due to an effect of the tumor from ulceration due to trauma, which would be expected not to have the same prognostic import. Future studies are required to analyze the prognostic value of COE itself.

Diagnosis, Differential↗
PubMed2003

Determinants of BRAF mutations in primary melanomas.

The RAS/mitogen-activated protein kinase pathway sends external growth-promoting signals to the nucleus. BRAF, a critical serine/threonine kinase in this pathway, is frequently activated by somatic mutation in melanoma. Using a cohort of 115 patients with primary invasive melanomas, we show that BRAF mutations are statistically significantly more common in melanomas occurring on skin subject to intermittent sun exposure than elsewhere (23 of 43 patients; P<.001, two-sided Fisher's exact test). By contrast, BRAF mutations in melanomas on chronically sun-damaged skin (1 of 12 patients) and melanomas on skin relatively or completely unexposed to sun, such as palms, soles, subungual sites (6 of 39 patients), and mucosal membranes (2 of 21 patients) are rare. We found no association of mutation status with clinical outcome or with the presence of an associated melanocytic nevus. The mutated BRAF allele was frequently found at an elevated copy number, implicating BRAF as one of the factors driving selection for the frequent copy number increases of chromosome 7q in melanoma. In summary, the uneven distribution of BRAF mutations strongly suggests distinct genetic pathways leading to melanoma. The high mutation frequency in melanomas arising on intermittently sun-exposed skin suggests a complex causative role of such exposure that mandates further evaluation.

Adult↗
PubMed2003

Understanding the progression of melanocytic neoplasia using genomic analysis: from fields to cancer.

Analysis of DNA copy number changes using comparative genomic hybridization in melanocytic neoplasms has revealed distinct patterns of chromosomal aberrations between benign melanocytic nevi and melanoma. Whereas the vast majority of melanoma expresses chromosomal aberrations, blue nevi, congenital nevi, and most Spitz nevi typically show no aberrations. A subset of Spitz nevi shows an isolated gain of chromosome 11p, an aberration pattern not observed in melanoma. These Spitz nevi frequently harbor mutations in the HRAS gene located on this chromosomal arm. Comparisons among melanoma types showed that melanomas of the palms, soles, and subungual sites can be distinguished by the presence of multiple gene amplifications that arise very early in their progression. About 50% of these amplifications are found at the cyclin D1 locus. By contrast, amplifications are significantly less frequent in other cutaneous melanoma types and if present arise late in progression. The frequent amplifications in melanomas on acral sites allowed the detection of single basal melanocytes with gene amplifications in the histologically normal appearing skin immediately adjacent to a melanoma. These "field cells" represent subtle melanoma in situ and are likely to represent minimal residual disease that can lead to local recurrences if not excised with safety margins. The high frequency of chromosomal aberrations in melanomas and their relative absence in nevi could indicate that melanocytes of melanomas went through telomeric crisis, whereas melanocytes in nevi did not. Such a scenario would suggest that replicative senescence is a tumor-suppressive mechanism in melanocytic neoplasia. It might also explain part of the phenomenon of regression commonly seen in melanoma. Genomic analysis is a powerful tool to obtain insight in the progression of melanocytic neoplasms with potential clinical applications for classification and detection of minimal residual melanoma.

Cell Transformation, Neoplastic↗
PubMed2003

Classifying melanocytic tumors based on DNA copy number changes.

Melanoma and benign melanocytic nevi can overlap significantly in their histopathological presentation and misdiagnoses are common. To determine whether genetic criteria can be of diagnostic help we determined DNA copy number changes in 186 melanocytic tumors (132 melanomas and 54 benign nevi) using comparative genomic hybridization. We found highly significant differences between melanomas and nevi. Whereas 127 (96.2%) of the melanomas had some form of chromosomal aberration, only 7 (13.0%) of the benign nevi cases had aberrations. All seven cases with aberrations were Spitz nevi, in six of which the aberration was an isolated gain involving the entire short arm of chromosome 11. This aberration was not observed in any of the 132 melanomas. We also analyzed the 132 melanomas for genetic differences depending on anatomical site, Clark's histogenetic type, and sun-exposure pattern. We show that melanomas on acral sites have significantly more aberrations involving chromosomes 5p, 11q, 12q, and 15, as well as focused gene amplifications. Melanomas classified as lentigo maligna melanomas or as occurring on severely sun-damaged skin showed markedly more frequent losses of chromosomes 17p and 13q. This study shows a pattern of chromosomal aberration in melanoma that is distinct from melanocytic nevi and should be further evaluated as a diagnostic test for melanocytic lesions that are now ambiguous. In addition, we show marked differences in the genetic make-up of melanomas that depend on anatomical location and sun-exposure pattern indicating that potential therapeutic targets might vary among melanoma types.

Adult↗
PubMed2003

Atypical junctional melanocytic proliferations in benign lichenoid keratosis.

Melanocytic lesions with lichenoid regression may mimic a benign lichenoid keratosis (BLK) histologically. A total of 336 BLKs were reviewed and deeper sections obtained to determine the frequency of this phenomenon. Two cases (0.6%) showed at least 1 melanocytic nest or junctional multinucleated melanocyte (starburst melanocyte) on deeper sections confirmed by MART-1 immunostaining. Both of these cases demonstrated solar elastosis, and 1 case had an effaced rete ridge pattern. Not included in the histological study are 5 additional cases in which the initial slide showed only lichenoid dermatitis, but deeper sections obtained before to the initial sign-out revealed a melanocytic proliferation. These 5 cases would have been signed out as "consistent with BLK" if deeper sections had not been obtained. Fluorescent in situ hybridization (FISH) was performed on 3 cases; in each case, the melanocytes demonstrated a loss of chromosome 9p21 DNA copy number. The finding of nests of genetically altered melanocytes on severely sun-damaged skin strongly suggests that these cases represent lichenoid regression of melanoma in situ. Pathologists should approach a diagnosis of BLK cautiously in the setting of severely sun-damaged skin.

Aged↗
PubMed2003

Two cases of unusual acral melanocytic tumors: illustration of molecular cytogenetics as a diagnostic tool.

The differential diagnosis between benign Spitz nevus and malignant melanoma may present considerable difficulties in some cases. Here we report 2 unusual melanocytic tumors with spitzoid features developing in acral sites of Japanese patients to illustrate the use of comparative genomic hybridization (CGH) to classify these lesions. Case 1 was a 12-mm-thick, >2 cm-diameter nodule on the sole of a 37-year-old man. Case 2 was a subungual tumor of the left index finger in a 13-year-old boy. CGH showed absence of chromosomal aberrations in case 1 and multiple aberrations in case 2, including focused amplification as previously described in acral melanomas. Case 1 was free of disease after 2.5 years of follow-up, whereas case 2 developed lymph node metastasis. We conclude that molecular techniques such as CGH can be of diagnostic help in the classification of histologically ambiguous lesions.

Adolescent↗