Li–Fraumeni syndrome in a Malaysian kindred

Ariffin, Hany; Martel‐Planche, Ghyslaine; Daud, Siti Sarah; Ibrahim, Kamariah; Hainaut, Pierre

doi:10.1016/j.cancergencyto.2008.06.004

Cited by 14 publications

(8 citation statements)

References 15 publications

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“…1) (11). This family showed a clear tendency for accelerated cancer onset over three successive generations, with a probable (unconfirmed) carrier grandmother who developed breast cancer at age 38, a carrier mother who developed bilateral breast cancer at age 26-27, and a sister who developed osteosarcoma at age 26, and carrier children who developed rhabdomyosarcoma at age 8 mo and adrenal cortical carcinoma at age 6 mo, whereas two other siblings and two cousins are carriers who have yet to develop a cancer (current ages [6][7][8][9][10][11][12][13][14].…”

Section: Resultsmentioning

confidence: 99%

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

Ariffin

Hainaut

Puzio-Kuter

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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 associated with 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.Li-Fraumeni syndrome | whole genome sequencing | genetic anticipation | p53 mutation | copy number variation

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Section: Resultsmentioning

confidence: 99%

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

Ariffin

Hainaut

Puzio-Kuter

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Upon further analysis, it was found that this family was previously tested in the same hospital for TP53 mutations due to the presence of the childhood cancers. Further analyses have revealed two unaffected children and an unaffected brother as TP53 carriers, in addition to her two affected children and her younger sister with osteosarcoma [19]. …”

Section: Resultsmentioning

confidence: 99%

Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients

et al. 2012

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IntroductionGermline TP53 mutations cause an increased risk to early-onset breast cancer in Li-Fraumeni syndrome (LFS) families and the majority of carriers identified through breast cancer cohorts have LFS or Li-Fraumeni-like (LFL) features. However, in Asia and in many low resource settings, it is challenging to obtain accurate family history and we, therefore, sought to determine whether the presence of early-onset breast cancer is an appropriate selection criteria for germline TP53 testing.MethodsA total of 100 patients with early-onset breast cancer (≤ 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in BRCA1, BRCA2 and TP53 by full DNA sequencing. Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues.ResultsWe identified 11 BRCA1 (11%) and 6 BRCA2 (6%) germline carriers among early-onset breast cancer patients. Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in TP53. Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH). Notably, E285K was found in two unrelated individuals and haplotype analyses suggest a founder effect. Two of the three intronic variants are likely benign based on their prevalence in a control population. Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers.ConclusionsOur study reports germline BRCA1, BRCA2 and TP53 mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that TP53 mutation screening should be considered for these patients. However, we find that even in low resource Asian settings where family history is poorly reported, germline TP53 mutations are found predominantly among breast cancer patients with a family history of LFS-linked cancers.

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“…ACC has been described developing synchronously with or subsequently to rhabdomyosarcoma in children with LiFraumeni syndrome, 9,22 and ACC and embryonal rhabdomyosarcoma have been reported separately in siblings as infants in a family with Li-Fraumeni syndrome. 4 Patients with Beckwith-Wiedemann syndrome also have a high incidence of ACC and rhabdomyosarcoma, among other tumors. This patient, however, had no family history of note.…”

Section: Discussionmentioning

confidence: 98%

Oncocytic Adrenal Cortical Carcinosarcoma With Pleomorphic Rhabdomyosarcomatous Metastases

Thway

Olmos

Shah

et al. 2012

American Journal of Surgical Pathology

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Adrenal cortical carcinosarcoma is a rare variant of adrenal cortical carcinoma. Sarcomatous change in adrenal cortical carcinomas is exceptionally rare, with only 9 cases previously described. Adrenal cortical carcinosarcomas tend to be aggressive tumors, with locoregional recurrence and rapid metastases from the sarcomatoid component. We describe what seems to be the first case of sarcoma arising in oncocytic adrenal cortical carcinoma. The sarcomatous component here was pleomorphic rhabdomyosarcoma. This occurred in a 45-year-old man who had nodal and pulmonary metastases of the rhabdomyosarcomatous component at presentation and who died of progressive disease 11 months later. Here, we discuss the clinical, radiologic, and pathologic findings and review the literature on adrenal cortical carcinosarcomas.

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Li–Fraumeni syndrome in a Malaysian kindred

Cited by 14 publications

References 15 publications

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

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

Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients

Oncocytic Adrenal Cortical Carcinosarcoma With Pleomorphic Rhabdomyosarcomatous Metastases

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