Gonadal mosaicism and familial adenomatous polyposis

Schwab, Angela L.; Tuohy, Thérèse M.F.; Condie, Michelle; Neklason, Deborah W.; Burt, Randall W.

doi:10.1007/s10689-007-9169-1

Cited by 31 publications

(12 citation statements)

References 23 publications

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“…Gonadal mosaicism, although rare, has been observed in other cancers. These include colorectal cancer, associated with familial adenomatous polyposis and mutation in the adenomatous polyposis coli ( APC ) gene; retinoblastoma and neurofibromatosis type 1 [26–28]. …”

Section: Discussionmentioning

confidence: 99%

Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors

Eaton

Tooke

Wainwright

et al. 2010

Pediatric Blood & Cancer

340

260

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Background Germline mutations and deletions of SMARCB1/INI1 in chromosome band 22q11.2 predispose patients to rhabdoid tumor and schwannomatosis. Previous estimates suggested that 15–20% of rhabdoid tumors were caused by an underlying germline abnormality of SMARCB1. However, these studies were limited by case selection and an inability to detect intragenic deletions and duplications. Procedure One hundred matched tumor and blood samples from patients with rhabdoid tumors of the brain, kidney, or soft tissues were analyzed for mutations and deletions of SMARCB1 by FISH, multiplex ligation-dependent probe amplification (MLPA), sequence analysis and high resolution Illumina 610K SNP based oligonucleotide array studies. Results Thirty-five of 100 patients were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions including regions both proximal and distal to SMARCB1. There were 9 cases that demonstrated parent to child transmission of a mutated copy of SMARCB1. In 8 of the 9 cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma, and 2 of the 8 families presented with multiple affected children in a manner consistent with gonadal mosaicism. Conclusions Approximately one third of newly diagnosed patients with rhabdoid tumor have an underlying genetic predisposition to tumors due to a germline SMARCB1 alteration. Families may demonstrate incomplete penetrance and gonadal mosaicism, which must be considered when counseling families of patients with rhabdoid tumor.

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Section: Discussionmentioning

confidence: 99%

Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors

Eaton

Tooke

Wainwright

et al. 2010

Pediatric Blood & Cancer

340

260

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“…It is postulated that mitotic errors and/or mutational events during development, adolescence, and adulthood result in genomically divergent cells, which, in turn, clonally expand to achieve a stable subset. Interestingly, genetic mosaicism has been noted in mitochondrial DNA 3–5 as well as in the germline DNA of gametes 6–12 and somatic cells 13–15 . Furthermore, each of these types of mosaicism can give rise to phenotypic heterogeneity, resulting in a range of outcomes, including disease severity depending on the developmental timing of the mutation, cell lineages affected, genetic locations included, and relative percentage of the cellular sub-populations 16 .…”

Section: Introductionmentioning

confidence: 99%

Detectable Clonal Mosaicism in the Human Genome

Machiela

Chanock

2013

Seminars in Hematology

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Human genetic mosaicism is the presence of two or more cellular populations with distinct genotypes in an individual who developed from a single fertilized ovum. While initially observed across a spectrum of rare genetic disorders, detailed assessment of data from genome-wide association studies now reveal that detectable clonal mosaicism involving large structural alterations (> 2 Mb) can also be seen in populations of apparently healthy individuals. The first generation of descriptive studies have generated new interest in understanding the molecular basis of the affected genomic regions, percent of the cellular subpopulation involved, and developmental timing of the underlying mutational event, which could reveal new insights into the initiation, clonal expansion and phenotypic manifestations of mosaic events. Early evidence indicates detectable clonal mosaicism increases in frequency with age and could preferentially occur in males. The observed pattern of recurrent events affecting specific chromosomal regions indicates some regions are more susceptible to these events, which could reflect inter-individual differences in genomic stability. Moreover, it is also plausible that the presence of large structural events could be associated with cancer risk. The characterization of detectable genetic mosaicism reveals that there could be important dynamic changes in the human genome associated with the aging process, which could be associated with risk for common disorders, such as cancer, cardiovascular disease, diabetes, and neurological disorders.

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“…A de novo mutation in a child might represent gonadal mosaicism and possibly also somatic mosaicism, in a mildly affected parent and thus entail a recurrence risk for siblings. Recently, a case of gonadal mosaicism with nonaffected parents was also described in a FAP family [Schwab et al, 2008]. In addition, disease severity may vary among individuals depending on whether the mutation occurs early or late in embryogenesis.…”

Section: Introductionmentioning

confidence: 99%

Parallel sequencing used in detection of mosaic mutations: Comparison with four diagnostic DNA screening techniques

et al. 2009

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We have made an evaluation of mutation detection techniques for their abilities to detect mosaic mutations. In this study, Sanger sequencing, single-strand conformation polymorphism (SSCP)/heteroduplex analysis (HD), protein truncation test (PTT), and denaturating high-performance liquid chromatography (DHPLC) were compared with parallel sequencing. In total DNA samples from nine patients were included in this study. Mosaic mutations were artificially constructed from seven of these samples, which were from heterozygote mutation carriers with the mutant allele present at 50%. The mutations analyzed were as follows: c.646C>T, c.2626C>T, c.2828C>A, c.1817_1818insA, c.2788dupA, c.416_419delAAGA, and c.607delC in the APC gene. The lowest degree of mutant alleles detected with SSCP/HD and DHPLC varied between 5% and 25%, and between 15% and 50% for Sanger sequencing. Three of the mutations were analyzed with PTT with considerable variations in detection levels (from 10 to 100%). Using parallel sequencing a detection frequency down to 1% was reached, but to achieve this high sensitivity sufficient coverage was required. Two patients with natural mosaic mutations were also included in this study. These two mutations had previously been identified with Sanger sequencing (NF2 c.1026_1027delGA) and SSCP/HD (APC c.2700_2701delTC). In conclusion, all the evaluated methods are applicable for mosaic mutation screening even though combinations of the conventional methods should be used to reach an adequate sensitivity. Sanger sequencing alone is not sensitive enough to detect low mosaic levels. Parallel sequencing seems to be the ultimate choice but the possibilities to use this technique is today limited by its complexity, economics, and availability of instruments.

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Gonadal mosaicism and familial adenomatous polyposis

Cited by 31 publications

References 23 publications

Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors

Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors

Detectable Clonal Mosaicism in the Human Genome

Parallel sequencing used in detection of mosaic mutations: Comparison with four diagnostic DNA screening techniques

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