RESUMEN
Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (ORâ=â1.27, 95% CI: 1.13-1.43, pâ=â6.77×10(-5)), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (ORâ=â0.51, 95% CI: 0.34-0.77, pâ=â0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL.
Asunto(s)
Reparación del ADN/genética , Predisposición Genética a la Enfermedad/genética , Linfoma no Hodgkin/genética , Polimorfismo de Nucleótido Simple , Epistasis Genética/genética , Genómica , Humanos , Sitios de Carácter Cuantitativo/genéticaRESUMEN
BACKGROUND: SLX4 encodes a DNA repair protein that regulates three structure-specific endonucleases and is necessary for resistance to DNA crosslinking agents, topoisomerase I and poly (ADP-ribose) polymerase (PARP) inhibitors. Recent studies have reported mutations in SLX4 in a new subtype of Fanconi anemia (FA), FA-P. Monoallelic defects in several FA genes are known to confer susceptibility to breast and ovarian cancers. METHODS AND RESULTS: To determine if SLX4 is involved in breast cancer susceptibility, we sequenced the entire SLX4 coding region in 738 (270 Jewish and 468 non-Jewish) breast cancer patients with 2 or more family members affected by breast cancer and no known BRCA1 or BRCA2 mutations. We found a novel nonsense (c.2469G>A, p.W823*) mutation in one patient. In addition, we also found 51 missense variants [13 novel, 23 rare (MAF<0.1%), and 15 common (MAF>1%)], of which 22 (5 novel and 17 rare) were predicted to be damaging by Polyphen2 (scoreâ=â0.65-1). We performed functional complementation studies using p.W823* and 5 SLX4 variants (4 novel and 1 rare) cDNAs in a human SLX4-null fibroblast cell line, RA3331. While wild type SLX4 and all the other variants fully rescued the sensitivity to mitomycin C (MMC), campthothecin (CPT), and PARP inhibitor (Olaparib) the p.W823* SLX4 mutant failed to do so. CONCLUSION: Loss-of-function mutations in SLX4 may contribute to the development of breast cancer in very rare cases.
Asunto(s)
Neoplasias de la Mama/genética , Mutación , Recombinasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Línea Celular , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad/genética , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (P(LYM)â=â3.89×10(-8), ORâ=â1.29) and rs948562 (P(LYM)â=â5.85×10(-7), ORâ=â1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, P(NHL)â=â5.72×10(-7)) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (P(FL)â=â2.69×10(-12), ORâ=â1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Leucemia Linfoide/genética , Sitios de Carácter Cuantitativo , Alelos , Línea Celular Tumoral , Cromosomas Humanos Par 11 , Expresión Génica , Humanos , Leucemia Linfoide/patología , Linfoma Folicular , Polimorfismo de Nucleótido SimpleRESUMEN
Although heritable factors are an important determinant of risk of early-onset cancer, the majority of these malignancies appear to occur sporadically without identifiable risk factors. Germline de novo copy-number variations (CNVs) have been observed in sporadic neurocognitive and cardiovascular disorders. We explored this mechanism in 382 genomes of 116 early-onset cancer case-parent trios and unaffected siblings. Unique de novo germline CNVs were not observed in 107 breast or colon cancer trios or controls but were indeed found in 7% of 43 testicular germ cell tumor trios; this percentage exceeds background CNV rates and suggests a rare de novo genetic paradigm for susceptibility to some human malignancies.
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Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Genómica/métodos , Mutación de Línea Germinal/genética , Neoplasias Testiculares/genética , Adulto , Humanos , Masculino , Padres , Proyectos de InvestigaciónRESUMEN
BACKGROUND: Germline mutations in the BRCA2 cancer susceptibility gene are associated with an increased risk of pancreatic cancer (PC). Breast-pancreas cancer families with BRCA1 mutations have also been observed. The influence of a family history (FH) of PC on BRCA mutation prevalence in patients with breast cancer (BC) is unknown. METHODS: A clinical database review (2000-2009) identified 211 Ashkenazi Jewish (AJ) BC probands who 1) underwent BRCA1/2 mutation analysis by full gene sequencing or directed testing for Ashkenazi founder mutations (BRCA1: 185delAG and 5382insC; BRCA2: 6174delT) and 2) had a FH of PC in a first-, second-, or third-degree relative. For each proband, the pretest probability of identifying a BRCA1/2 mutation was estimated using the Myriad II model. The observed-to-expected (O:E) mutation prevalence was calculated for the entire group. RESULTS: Of the 211 AJ BC probands with a FH of PC, 30 (14.2%) harbored a BRCA mutation. Fourteen (47%) of the mutations were in BRCA1 and 16 (53%) were in BRCA2. Patients diagnosed with BC at age ≤ 50 years were found to have a higher BRCA1/2 mutation prevalence than probands with BC who were diagnosed at age > 50 years (21.1% vs 6.9%; P = .003). In patients with a first-, second-, or third-degree relative with PC, mutation prevalences were 15.4%, 15.3%, and 8.6%, respectively (P = .58). In the overall group, the observed BRCA1/2 mutation prevalence was 14.2% versus an expected prevalence of 11.8% (O:E ratio, 1.21; P = .15). CONCLUSIONS: BRCA1 and BRCA2 mutations are observed with nearly equal distribution in AJ breast-pancreas cancer families, suggesting that both genes are associated with PC risk. In this population, a FH of PC was found to have a limited effect on mutation prevalence.
Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutación de Línea Germinal , Judíos/genética , Neoplasias Pancreáticas/genética , Anciano , Neoplasias de la Mama/epidemiología , Salud de la Familia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/epidemiología , PrevalenciaRESUMEN
Genome-wide association studies (GWAS) have now been performed in nearly all common malignancies and have identified more than 100 common genetic risk variants that confer a modest increased risk of cancer. For most discovered germline risk variants, the per allele effect size is small (<1.5) and the biologic mechanism of the detected association remains unexplained. Exceptions are the risk variants identified in JAK2 in myeloproliferative neoplasm and in the KITLG gene in testicular cancer, which are each associated with nearly a 3-fold increased risk of disease. GWAS have provided an efficient approach to identifying common, low-penetrance risk variants, and have implicated several novel cancer susceptibility loci. However, the identified low-penetrance risk variants explain only a small fraction of the heritability of cancer and the clinical usefulness of using these variants for cancer-risk prediction is to date limited. Studies involving more heterogeneous populations, determination of the causal variants, and functional studies are now necessary to further elucidate the potential biologic and clinical significance of the observed associations.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias/genética , Pruebas Genéticas , HumanosRESUMEN
A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2-4% of such families. The extent to which major genomic rearrangements in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4-88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.