Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome

Hany Ariffin; Pierre Hainaut; Anna Puzio-KuterSoo Sin ChoongAdelyne Sue Li ChanDenis TolkunovGunaretnam RajagopalWenfeng KangLeon Li Wen LimShekhar KrishnanKok-Siong ChenMaria Isabel AchatzMawar KarsaJannah ShamsaniArnold J. LevineChang S. Chan

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome

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Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome

机译：Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome

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The Li–Fraumeni syndrome (LFS) and its variant form (LFL) is a familial predisposition to multiple forms of childhood, adolescent, and adult cancers associatedwith germ-line mutation in the TP53 tumor suppressor gene. Individual disparities in tumor patterns are compounded by acceleration of cancer onset with successive generations. It has been suggested that this apparent anticipation pattern may result from germ-line genomic instability in TP53 mutation carriers, causing increased DNA copy-number variations (CNVs) with successive generations. To address the genetic basis of phenotypic disparities of LFS/LFL, we performed whole-genome sequencing (WGS) of 13 subjects from two generations of an LFS kindred. Neither de novo CNV nor significant difference in total CNV was detected in relation with successive generations or with age at cancer onset. These observations were consistent with an experimental mouse model system showing that trp53 deficiency in the germ line of father or mother did not increase CNV occurrence in the offspring. On the other hand, individual records on 1,771 TP53 mutation carriers from 294 pedigrees were compiled to assess genetic anticipation patterns (International Agency for Research on Cancer TP53 database). No strictly defined anticipation pattern was observed. Rather, in multigeneration families, cancer onset was delayed in older compared with recent generations. These observations support an alternative model for apparent anticipation in which rare variants from noncarrier parents may attenuate constitutive resistance to tumorigenesis in the offspring of TP53 mutation carriers with late cancer onset.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第43期|15497-15501|共5页
作者
Hany Ariffin; Pierre Hainaut; Anna Puzio-KuterSoo Sin ChoongAdelyne Sue Li ChanDenis TolkunovGunaretnam RajagopalWenfeng KangLeon Li Wen LimShekhar KrishnanKok-Siong ChenMaria Isabel AchatzMawar KarsaJannah ShamsaniArnold J. LevineChang S. Chan;
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作者单位

University of Malaya Cancer Research Institute, University of Malaya, 50603 Kuala Lumpur, Malaysia;

International Prevention Research Institute, 69006 Lyon, France;

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901Paediatric Haematology-Oncology Unit, University of Malaya Medical Centre, Kuala Lumpur, MalaysiaDepartment of Oncogenetics, International Research Center, AC Camargo Cancer Center, National Institute of Oncogenomics, 01508-010, Sao Paulo, BrazilInstitute for Advanced Study, Princeton, NJ 08540;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Li–Fraumeni syndrome; whole genome sequencing; genetic anticipation; p53 mutation; copy number variation;

Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome

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