High incidence of skewed X chromosome inactivation in young patients with familial non-BRCA1/BRCA2 breast cancer

Kristiansen, Marianne; Knudsen, Gun Peggy; Maguire, Pierce; Margolin, Sara; Pedersen, Jan; Lindblom, Annika; Ørstavik, Karen Helene

doi:10.1136/jmg.2005.032433

Cited by 47 publications

(51 citation statements)

References 20 publications

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“…One study reported a higher frequency of skewed X-inactivation in young breast cancer patients with a family history of breast cancer, but no BRCA1/2 mutations, compared to controls. Howeveer, skewed X-inactivation frequency did not differ significantly between BRCA1/2 mutation carriers and age-matched healthy controls [41]. We did not perform X-inactivation analysis in our study.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor htSNPs in relation to androgen levels and OC use in young women from high-risk breast cancer families

Hietala

Henningson

Törngren

et al. 2011

Molecular Genetics and Metabolism

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"Androgen receptor htSNPs in relation to androgen levels and OC use in young women from high-risk breast cancer families." AbstractHigh testosterone levels have been associated with breast cancer. BRCA1 may function as an androgen receptor (AR) co-regulator. We aimed to examine AR haplotype-tagging singlenucleotide polymorphisms (AR htSNPs) and diplotypes in relation to in vivo androgen levels, combined OC use, CAG and GGC genotypes, and BRCA1/2/X family status in 269 young healthy women from breast cancer high-risk families and 56 additional BRCA1/2 mutation carriers. Testosterone, androstenedione, dehydroepiandrosterone sulfate and body constitution were measured on cycle days 18-23. Six AR htSNPs, and CAG and GGC repeat lengths were genotyped. Most OC users had lower androgen levels than non-users (all Ps<0.0001). Rare variant diplotypes were associated with higher testosterone levels in OC users than in nonusers (P interaction =0.011). The interaction remained after adjustment for family clustering. Neither individual AR htSNPs nor other diplotypes were significantly associated with androgen levels and did not tag for CAG or GGC genotypes. In the first included woman from each family, the odds of having the most common diplotype was lower in BRCA1 families compared to other families OR 0.41 (95%CI 0.22-0.78). In conclusion we found few associations between AR htSNPs or diplotypes and androgen levels in women. Diplotypes cannot replace genotyping of microsatellites CAG or GGC. Since testosterone levels are not affected the same way by combined OC use among all women, young women who have higher testosterone levels during combined OC use may belong to the subgroup of women who will not be helped by combined OCs for treatment of androgen dependent conditions and may be at higher risk for early-onset breast cancer. Whether these women can be identified with AR genotyping needs to be confirmed in an independent cohort.Key words: androgen receptor polymorphisms / androgens / oral contraceptives / BRCA / premenopausal women AR htSNPs, androgen hormones and OC use M. Hietala

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Section: Discussionmentioning

confidence: 99%

Androgen receptor htSNPs in relation to androgen levels and OC use in young women from high-risk breast cancer families

Hietala

Henningson

Törngren

et al. 2011

Molecular Genetics and Metabolism

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“…Although less well studied than somatic mutations and LOH, both X chromosome inactivation (42,43) and RNA editing (44) (i.e., a posttranscriptional process that alters the information encoded in gene transcripts, in this case a nsSNV present in the mRNA but not the gDNA) have been previously linked to cancer but not MPM (45). The actual editing is site-specific and occurs through specific mechanisms that are thought to be altered in cancers (44).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome sequencing of malignant pleural mesothelioma tumors

Sugarbaker

Richards²,

Gordon³

et al. 2008

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

141

116

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Cancers arise by the gradual accumulation of mutations in multiple genes. We now use shotgun pyrosequencing to characterize RNA mutations and expression levels unique to malignant pleural mesotheliomas (MPMs) and not present in control tissues. On average, 266 Mb of cDNA were sequenced from each of four MPMs, from a control pulmonary adenocarcinoma (ADCA), and from normal lung tissue. Previously observed differences in MPM RNA expression levels were confirmed. Point mutations were identified by using criteria that require the presence of the mutation in at least four reads and in both cDNA strands and the absence of the mutation from sequence databases, normal adjacent tissues, and other controls. In the four MPMs, 15 nonsynonymous mutations were discovered: 7 were point mutations, 3 were deletions, 4 were exclusively expressed as a consequence of imputed epigenetic silencing, and 1 was putatively expressed as a consequence of RNA editing. Notably, each MPM had a different mutation profile, and no mutated gene was previously implicated in MPM. Of the seven point mutations, three were observed in at least one tumor from 49 other MPM patients. The mutations were in genes that could be causally related to cancer and included XRCC6, PDZK1IP1, ACTR1A, and AVEN.DNA sequencing ͉ tumor mutations ͉ lung cancer ͉ bioinformatics ͉ loss of heterozygosity B ecause cancer arises as a consequence of multiple mutations, human cancer genomes are being sequenced to identify the mechanisms of tumorigenesis. Pilot sequencing studies include recent exon resequencing of tumors and cell lines that revealed somatic mutations in hundreds of genes not previously implicated in oncogenesis. These studies generally focused on a single class of mutations such as point mutations in coding regions of preselected candidate genes, and the results so far indicate that even within similar histological classes, tumors possess unique mutational profiles (1-3). However, there has rarely been an analysis of whether a mutated gene is actually expressed in the tumor cell nor has there been an attempt to use sequencing to identify other types of mutations such as chromosomal deletions or translocation (4, 5) or loss of heterozygosity related to epigenetic silencing (6, 7). Moreover, no unbiased deep sequencing analysis of all expressed genes in cancer tissues has been reported to date.Malignant pleural mesothelioma (MPM) is an asbestosrelated, rapidly fatal cancer. Its genetic basis is unknown but appears to involve multiple types of chromosomal abnormalities (5,(8)(9)(10)(11)(12)(13)(14). Central mechanisms underlying MPM are unclear, although MPM tumors evoke a strong inflammatory response thought to contribute to tumorigenesis (15). In addition, tumor cell survival promoted by TNF-␣ responsive antiapoptotic proteins such as Inhibitor of Apoptosis-1 (IAP-1) facilitates the resistance of MPM to most cytotoxic chemotherapeutic drugs (16). Expression profiling with microarrays has supported the general role of inflammation in MPM etiology and has provided...

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“…Little is known about X inactivation and common diseases, except for breast cancer, which has been widely studied, but with inconsistent results. [31][32][33][34][35] …”

Section: Discussionmentioning

confidence: 99%

Skewed X inactivation and survival: a 13-year follow-up study of elderly twins and singletons

Mengel‐From

Thinggaard²,

Christiansen³

et al. 2011

Eur J Hum Genet

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In mammalian females, one of the two X chromosomes is inactivated in early embryonic life. Females are therefore mosaics for two cell populations, one with the maternal and one with the paternal X as the active X chromosome. A skewed X inactivation is a marked deviation from a 50:50 ratio. In populations of women past 55-60 years of age, an increased degree of skewing (DS) is found. Here the association between age-related skewing and mortality is analyzed in a 13-year follow-up study of 500 women from three cohorts (73-100 years of age at intake). Women with low DS had significantly higher mortality than the majority of women who had a more skewed DS (hazard ratio: 1.30; 95% CI: 1.04-1.64). The association between X inactivation and mortality was replicated in dizygotic twin pairs for which the co-twin with the lowest DS also had a statistically significant tendency to die first in the twin pairs with the highest intra-pair differences in DS (proportion: 0.71; 95% CI: 0.52-0.86). Both results suggest that lower DS is associated with higher mortality. We therefore propose that age-related skewing may be partly due to a population selection with lower mortality among those with higher DS. European Journal of Human Genetics (2012) 20, 361-364; doi:10.1038/ejhg.2011.215; published online 7 December 2011Keywords: aging; sex; mortality INTRODUCTIONThe biological phenomenon of X-chromosome inactivation is observed in females across a variety of mammalian species. Females have two X chromosomes, of which either the maternal or the paternal X is inactivated in early embryonic life, at about the time of implantation. 1 Females are therefore mosaics for two cell populations, one with the maternal and one with the paternal X as the active X chromosome. Early in life the two cell populations are normally distributed around a 50:50 ratio. 2,3 In some females, one of the two cell populations is more abundant than the other and the value of the larger proportion is called the degree of skewing (DS), with DSZ50. DS¼50 is therefore a complete random X inactivation and DS¼100 is a completely skewed X inactivation. X inactivation is believed to occur randomly for each cell and to be permanent for all descendants of the cell. For women younger than 55-60 years of age, DS does not increase significantly with age in populations 2,3 or within the same individual. 4 However, DS increases considerably with age in cross-sectional studies of populations older than 55-60 years and this age association continues to increase in populations at the most advanced ages. 2,3,5 Most X-inactivation studies have been performed on peripheral blood cells, but a higher frequency of skewed X inactivation in elderly women has also been found in buccal swab cells. 6,7 Most X-inactivation studies use an indirect assay targeted to a methylation site and polymorphic sequence named the HUMARA assay. The representativeness of this indirect method for studying X inactivation has been questioned. Recently, however, skewing of X inactivation in aging women was co...

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High incidence of skewed X chromosome inactivation in young patients with familial non-BRCA1/BRCA2 breast cancer

Cited by 47 publications

References 20 publications

Androgen receptor htSNPs in relation to androgen levels and OC use in young women from high-risk breast cancer families

Androgen receptor htSNPs in relation to androgen levels and OC use in young women from high-risk breast cancer families

Transcriptome sequencing of malignant pleural mesothelioma tumors

Skewed X inactivation and survival: a 13-year follow-up study of elderly twins and singletons

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