PMS2 c.2117del (p.Lys706Serfs*19) is the Most Frequent Cancer-Associated Founder Pathogenic Variant in the French-Canadian Population of Quebec, Canada.

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Anne-Laure Chong, Alejandro Mejia-Garcia, Supriya Behl, Zaki El Haffaf, Sébastien Chénier, Bruno Maranda, Valérie Désilets, Sébastien Lévesque, Lysanne Castonguay, Anne-Marie Mes-Masson, Sylvie Giroux, François Rousseau, Nancy Hamel, George Chong, Simon Gravel, William D Foulkes
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引用次数: 0

Abstract

We identified a PMS2 variant (NM_000535.7:c.2117del, p.Lys706Serfs*19) in 22 French-Canadian (FC) families from Quebec with Lynch syndrome (LS; n = 21) or constitutional mismatch repair deficiency (CMMRD; n = 1). We aimed to (a) confirm its founder origin, (b) assess its allele frequency in the FC population, and (c) determine its contribution to the risk of developing various cancers in this population. We identified a haplotype common to all c.2117del alleles spanning 666 kb to 1.37 Mb, confirming the founder nature of the variant. In affected cases, the variant was found in 0 out of 821 breast cancer cases, 8 out of 693 (1.15%) endometrial cancer (EC) cases, and 1 out of 191 (0.52%) colorectal cancer (CRC) cases. In unaffected persons, the variant was identified in 22/6347 newborns (0.35%) and in 21/18129 FC CARTaGENE cohort participants (0.12%). Within this cohort, an excess of CRC (odds ratio: 10.7; 95% CI: 1.42-80.1; p value = 0.022), but not EC, was seen among heterozygotes for the PMS2 founder variant. Analysis of the variant in 24 subregions of Quebec showed over-representation in 5 of them. Here, we report the most frequent genetic cause of mismatch repair deficiency syndromes identified thus far in the FC population of Quebec.

PMS2 c.2117del (p.Lys706Serfs*19)是加拿大魁北克法裔加拿大人群中最常见的癌症相关始发致病变异。
我们发现了一个PMS2变体(NM_000535.7:c)。2117del, p.Lys706Serfs*19)在魁北克22个法裔加拿大人(FC)家族与Lynch综合征(LS;n = 21)或体质错配修复缺陷(CMMRD;n = 1)。我们的目的是(a)确认其创始起源,(b)评估其在FC人群中的等位基因频率,以及(c)确定其对该人群中发生各种癌症的风险的贡献。我们发现了一个c.2117del等位基因共有的单倍型,跨度为666 kb到1.37 Mb,证实了该变异的创始性质。在受影响的病例中,821例乳腺癌中有0例,693例子宫内膜癌(EC)中有8例(1.15%),191例结直肠癌(CRC)中有1例(0.52%)发现该变异。在未受影响的人群中,22/6347新生儿(0.35%)和21/18129 FC CARTaGENE队列参与者(0.12%)中发现了该变异。在该队列中,CRC(优势比:10.7;95% ci: 1.42-80.1;p值= 0.022),但在PMS2始创变异的杂合子中未见EC。对魁北克省24个次区域的变异分析表明,其中5个区域的代表性过高。在这里,我们报告了迄今为止在魁北克FC人群中发现的错配修复缺陷综合征最常见的遗传原因。
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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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