RESUMEN
PURPOSE: We report the largest study to date analyzing the risk of cancers other than melanoma in melanoma families positive for the same CDKN2A mutation. EXPERIMENTAL DESIGN: We studied family members of 22 families positive for the p16-Leiden founder mutation who had attended a surveillance clinic or were their close relatives. Within this cohort, observed and expected rates of cancer were computed by mutation status consisting of 221 (proven plus obligate) carriers, 639 (proven plus obligate) noncarriers, and 668 first-degree relatives whose carrier risk was estimated from the relationship to known carriers and the age and melanoma status of that person and their relatives. RESULTS: Our analysis shows a relative risk (RR) of cancer other than melanoma and nonmelanoma skin cancer of 4.4 [95% confidence interval (95% CI), 3.3-5.6], predominantly attributable to the increased risk for pancreatic cancer (RR, 46.6; 95% CI, 24.7-76.4), but also for other cancers. We provide substantial proof for pancreatic cancer being a key component of the p16-Leiden phenotype. Inclusion of this cancer in a penetrance analysis leads to an estimated RR of pancreatic cancer for mutation carriers of 47.8 (95% CI, 28.4-74.7). CONCLUSIONS: This study shows clear evidence of increased risk of cancers other than melanoma in CDKN2A families carrying the p16-Leiden mutation. Further research is necessary to determine if similar risks apply to families with CDKN2A mutations other than p16-Leiden.
Asunto(s)
Genes p16 , Predisposición Genética a la Enfermedad , Melanoma/genética , Neoplasia Endocrina Múltiple/epidemiología , Mutación , Neoplasias Cutáneas/genética , Femenino , Efecto Fundador , Humanos , Masculino , Medición de RiesgoRESUMEN
In most Dutch melanoma families, a founder deletion in the melanoma susceptibility gene CDKN2A (which encodes p16) is present. This founder deletion (p16-Leiden) accounts for a significant proportion of the increased melanoma risk. However, it does not account for the Atypical Nevus (AN) phenotype that segregates in both p16-Leiden carriers and non-carriers. The AN-affected p16-Leiden family members are therefore a unique valuable resource for unraveling the genetic etiology of the AN phenotype, which is considered both a risk factor and a precursor lesion for melanoma. In this study, we performed a genome-wide scan for linkage in four p16-Leiden melanoma pedigrees, classifying family members with five or more AN as affected. The strongest evidence for an atypical nevus susceptibility gene was mapped to chromosome band 7q21.3 (two-point LOD score=2.751), a region containing candidate gene CDK6.
Asunto(s)
Síndrome del Nevo Displásico/genética , Genes p16 , Ligamiento Genético/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Cromosomas Humanos Par 7/genética , Quinasa 6 Dependiente de la Ciclina/genética , Síndrome del Nevo Displásico/enzimología , Femenino , Efecto Fundador , Eliminación de Gen , Tamización de Portadores Genéticos , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Melanoma/enzimología , Linaje , Neoplasias Cutáneas/enzimologíaRESUMEN
Mutations in known breast cancer susceptibility genes account for a minority of the familial aggregation of the disease. To search for further breast cancer susceptibility genes, we performed a combined analysis of four genome-wide linkage screens, which included a total of 149 multiple case breast cancer families. All families included at least three cases of breast cancer diagnosed below age 60 years, at least one of whom had been tested and found not to carry a BRCA1 or BRCA2 mutation. Evidence for linkage was assessed using parametric linkage analysis, assuming both a dominant and a recessive mode of inheritance, and using nonparametric methods. The highest LOD score obtained in any analysis of the combined data was 1.80 under the dominant model, in a region on chromosome 4 close to marker D4S392. Three further LOD scores over 1 were identified in the parametric analyses and two in the nonparametric analyses. A maximum LOD score of 2.40 was found on chromosome arm 2p in families with four or more cases of breast cancer diagnosed below age 50 years. The number of linkage peaks did not differ from the number expected by chance. These results suggest regions that may harbor novel breast cancer susceptibility genes. They also indicate that no single gene is likely to account for a large fraction of the familial aggregation of breast cancer that is not due to mutations in BRCA1 or BRCA2.
Asunto(s)
Neoplasias de la Mama/genética , Ligamiento Genético , Predisposición Genética a la Enfermedad , Genoma Humano , Femenino , Genes BRCA1 , Genes BRCA2 , Pruebas Genéticas , Humanos , Escala de Lod , Masculino , Modelos EstadísticosRESUMEN
PURPOSE: Since the identification of BRCA1 and BRCA2, there has been no major breast cancer susceptibility gene discovered by linkage analysis in breast cancer families. This has been attributed to the heterogeneous genetic basis for the families under study. Recent studies have indicated that breast tumors arising in women carrying a BRCA1 mutation have distinct histopathologic, immunophenotypic, and genetic features. To a lesser extent, this is also true for breast tumors from BRCA2 carriers. This indicates that it might be possible to decrease the genetic heterogeneity among families in which BRCA1 and BRCA2 have been excluded with high certainty (BRCAx families) if distinct subgroups of BRCAx-related breast tumors could be identified. EXPERIMENTAL DESIGN: Loss of heterozygosity (LOH) analysis with at least one marker per chromosomal arm (65 markers) was used to characterize 100 breast tumors derived from 92 patients from 42 selected BRCAx families. In addition, the immunophenotype of 10 markers was compared with that of 31 BRCA1- and 21 BRCA2-related breast tumors. RESULTS AND CONCLUSIONS: The BRCAx-related tumors were characterized by more frequent LOH at 22q relative to sporadic breast cancer (P < 0.02), and differed significantly from BRCA1- and BRCA2-related tumors in their positivity for Bcl2. However, cluster analyses of the combined data (LOH and immunohistochemistry) did not result in subgroups that would allow meaningful subclassification of the families. On chromosomes 2, 3, 6, 12, 13, 21, and 22, we found markers at which LOH occurred significantly more frequent among the tumors from patients belonging to a single family than expected on the basis of overall LOH frequencies. Nonetheless, linkage analysis with markers for the corresponding regions on chromosomes 12, 21, and 22 did not reveal significant logarithm of the odds.
Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/patología , Pérdida de Heterocigocidad , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Cromosomas Humanos Par 22/genética , Análisis por Conglomerados , Salud de la Familia , Femenino , Ligamiento Genético , Genoma Humano/genética , Humanos , Inmunohistoquímica , Escala de Lod , Repeticiones de Microsatélite , Persona de Mediana Edad , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Proteína p53 Supresora de Tumor/análisisRESUMEN
Recently, a non-random transmission of BRCA1 mutant alleles to the off-spring of carriers has been suggested. If confirmed by further studies, the finding will have important implications both for risk assessment and the understanding of BRCA1 biology. However, these kind of analysis are not easy to perform due to several ascertainment biases inherent to the identification of BRCA1 carriers. In this report we propose different approaches to overcome such biases and we present additional data supporting a non-random transmission of BRCA1 mutant alleles.