Heramb Cecilie, Wangensteen Teresia, Grindedal Eli Marie, Ariansen Sarah Louise, Lothe Sheba, Heimdal Ketil Riddervold, Mæhle Lovise
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
University of Oslo, Oslo, Norway.
Hered Cancer Clin Pract. 2018 Jan 10;16:3. doi: 10.1186/s13053-017-0085-6. eCollection 2018.
Founder mutations in the two breast cancer genes, and , have been described in many populations, among these are Ashkenazi-Jewish, Polish, Norwegian and Icelandic. Founder mutation testing in patients with relevant ancestry has been a cost-efficient approach in such populations. Four Norwegian founder mutations were defined by haplotyping in 2001, and accounted for 68% of mutation carriers at the time. After 15 more years of genetic testing, updated knowledge on the mutation spectrum of both and in Norway is needed. In this study, we aim at describing the mutation spectrum and frequencies in the carrier population of the largest clinic of hereditary cancer in Norway.
A total of 2430 carriers from 669 different families, and 1092 carriers from 312 different families were included in a quality of care study. All variants were evaluated regarding pathogenicity following ACMG/ENIGMA criteria. The variants were assessed in AlaMut and supplementary databases to determine whether they were known to be founder mutations in other populations.
There were 120 different and 87 different variants among the mutation carriers. Forty-six per cent of the registered families (454/981) had a previously reported Norwegian founder mutation. The majority of mutations (71%) were rare, each found in only one or two families. Fifteen per cent of families and 25% of families had one of these rare variants. The four well-known Norwegian founder mutations previously confirmed through haplotyping were still the four most frequent mutations in carriers, but the proportion of mutation carriers accounted for by these mutations had fallen from 68 to 52%, and hence the founder effect was weaker than previously described.
The spectrum of and mutations in the carrier population at Norway's largest cancer genetics clinic is diverse, and with a weaker founder effect than previously described. As a consequence, retesting the families that previously have been tested with specific tests/founder mutation tests should be a prioritised strategy to find more mutation positive families and possibly prevent cancer in healthy relatives.
在两个乳腺癌基因（和）中发现的始祖突变已在许多人群中得到描述，其中包括德系犹太人、波兰人、挪威人和冰岛人。对具有相关血统的患者进行始祖突变检测在这些人群中是一种具有成本效益的方法。2001年通过单倍型分析确定了四个挪威始祖突变，当时占突变携带者的68%。经过15年多的基因检测，需要更新关于挪威和基因的突变谱的知识。在本研究中，我们旨在描述挪威最大的遗传性癌症诊所的携带者群体中的突变谱和频率。
一项医疗质量研究纳入了来自669个不同家庭的2430名携带者和来自312个不同家庭的1092名携带者。所有变异均按照ACMG/ENIGMA标准评估其致病性。这些变异在AlaMut和补充数据库中进行评估，以确定它们在其他人群中是否已知为始祖突变。
突变携带者中有120种不同的和87种不同的变异。登记的家庭中有46%（454/981）有先前报道的挪威始祖突变。大多数突变（71%）很罕见，每个仅在一两个家庭中发现。15%的家庭和25%的家庭有这些罕见变异之一。先前通过单倍型分析确认的四个著名的挪威始祖突变仍然是携带者中最常见的四个突变，但这些突变在突变携带者中所占的比例已从68%降至52%，因此始祖效应比先前描述的要弱。
挪威最大的癌症遗传学诊所的携带者群体中的和突变谱是多样的，始祖效应比先前描述的要弱。因此，对先前已通过特定检测/始祖突变检测进行检测的家庭进行重新检测应该是一项优先策略，以找到更多突变阳性家庭，并可能预防健康亲属患癌症。
