Linkage to the CDKN2A locus has been demonstrated in approximately 50% of families with hereditary malignant melanoma but only a subgroup of these harbor identified mutations. We here report a Norwegian melanoma-prone family with a novel large germline deletion removing 13707 bps of the CDKN2A gene, including exon 1alpha and approximately half of exon 2. Our finding is the first reported large CDKN2A germline deletion with a breakpoint located within an exon. This type of deletion is not detectable through the direct exon sequencing and may also escape identification by use of multiplex ligation-dependent probe amplification (MLPA) analysis. Here, the defect was identified through detection of a truncated p14(ARF) mRNA and loss of p16(INK4a) mRNA expression from the affected allele. Our finding suggests that atypical, large deletions in the CDKN2A gene may explain linkage to the 9p21 chromosome band without identified gene mutations among melanoma-prone families. Thus, it illustrates the need to include p14(ARF)- and p16(INK4a) transcript analysis when searching for unknown mutations within the CDKN2A locus in melanoma-prone families. Similar deletions with atypical breakpoints may affect other genes involved in cancer disposition, and the need to examine gene transcripts in high-risk families with no mutation identified through conventional testing should be considered.

译文

:与CDKN2A基因座的联系已在大约50%的遗传性恶性黑色素瘤家庭中得到证实,但这些港口中只有一个亚群可识别出突变。我们在此报告了一个挪威黑素瘤易感家族,该家族具有新颖的大种系缺失,删除了13707 bps的CDKN2A基因,包括外显子1alpha和外显子2的一半。 。通过直接外显子测序无法检测到这种类型的缺失,并且也可以通过使用多重连接依赖性探针扩增(MLPA)分析来逃避鉴定。在这里,缺陷的检测是通过检测受影响的等位基因中被截短的p14(ARF)mRNA和p16(INK4a)mRNA表达的缺失来确定的。我们的发现表明,CDKN2A基因中的非典型大缺失可能解释了与9p21染色体带的连锁,而黑素瘤易感家族中未发现基因突变。因此,它说明了在易发黑素瘤家族的CDKN2A基因座中寻找未知突变时,需要包括p14(ARF)-和p16(INK4a)转录本分析。具有非典型断点的类似缺失可能会影响涉及癌症治疗的其他基因,因此应考虑检查高危家庭中基因转录本的需要,而这些基因没有通过常规检测鉴定出的突变。

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