Genetic Anticipation Is Associated with Telomere Shortening in Hereditary Breast Cancer

Martı́nez-Delgado, Beatriz; Yanowsky, Kira; Inglada‐Pérez, Lucía; Domingo, Samuel; Urioste, Miguel; Osorio, Ana; Benı́tez, Javier

doi:10.1371/journal.pgen.1002182

Cited by 81 publications

(99 citation statements)

References 41 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%

“…Other genetic mechanisms that have been suggested include accumulation of copy-number variations (CNVs) with successive generations, a hallmark of germ-line genome instability, and progressive telomere shortening (8). The latter mechanisms have also been documented in pedigrees with anticipation features: namely, in breast cancer susceptibility syndromes (BRCA1 carriers) (9) and in Lynch syndrome (10).…”

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confidence: 99%

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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%

mentioning

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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“…Evidence that cell replication is limited by shorter TL has been reported in vitro (37)(38)(39)(40) through in vivo experimentation in animal models (41)(42)(43) and in cross-sectional and longitudinal observational studies (7)(8)(9)(10)(11)(12)(13)(44)(45)(46)(47)(48). On the other hand, whether inherited TL alters the risks of developing cancer is unsettled (20,21,(49)(50)(51)(52)(53), so the implications of the association of paternal ages at reproduction with TL for cancer risk are unclear. Direct assessment of the health implications of paternal-age effects on descendants' TL is lacking and awaits future study.…”

Section: Discussionmentioning

confidence: 99%

Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants

Eisenberg

Hayes

Kuzawa

2012

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

188

170

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Telomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes from nucleotide loss as cells divide. Telomere length (TL) shortens with age in most proliferating tissues, limiting cell division and thereby contributing to senescence. However, TL increases with age in sperm, and, correspondingly, offspring of older fathers inherit longer telomeres. Using data and samples from a longitudinal study from the Philippines, we first replicate the finding that paternal age at birth is associated with longer TL in offspring (n = 2,023, P = 1.84 × 10 −6 ). We then show that this association of paternal age with offspring TL is cumulative across multiple generations: in this sample, grandchildren of older paternal grandfathers at the birth of fathers have longer telomeres (n = 234, P = 0.038), independent of, and additive to, the association of their father's age at birth with TL. The lengthening of telomeres predicted by each year that the father's or grandfather's reproduction are delayed is equal to the yearly shortening of TL seen in middle-age to elderly women in this sample, pointing to potentially important impacts on health and the pace of senescent decline in tissues and systems that are cell-replication dependent. This finding suggests a mechanism by which humans could extend late-life function as average age at reproduction is delayed within a lineage.adaptation | epigenetics | evolution | parental effects | transgenerational plasticity T elomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes from nucleotide loss as cells divide (1). In many tissues, telomere lengths (TL) are shortened by cellular proliferation, and as a result TL tends to decline with age (2-5). As cell replication generally requires a minimal TL, shortened TL is thought to contribute to senescence (6). Consistent with this, elderly persons with shorter telomeres (in blood) for their age have reduced survival (7-13).Although it is well established that TL shortens with age in most proliferating tissues (e.g., 4, 5), sperm TL is an exceptionolder men have sperm with longer telomeres (4,14,15). This may be explained by the fact that the activity of telomerase (an enzyme that extends TL) is high in testes (16,17). Consistent with the fact that offspring inherit half their chromosomes from sperm, offspring of older fathers tend to have longer telomeres (4,18,19). In contrast, because the pool of ova is established in utero, TL in ova are thought to be stable with age, and there is no evidence for a maternal age effect on TL in offspring (e.g., 4, 20).We recently hypothesized that the age-related TL increase in sperm could lead to cumulative, and thus more biologically significant, multigenerational lengthening or shortening of TL in response to population trends in reproductive scheduling (21). If average reproductive age of recent patrilineal ancestors cumulatively influences TL, this might also lead to changes in TL of sufficient magnitude to influence late-life function and l...

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“…It is believed that the shortening of telomeres in cancer cells is also associated with characteristics and prognosis of cancer. Recently, telomere length has been reported to be associated with tumor size, lymph node metastasis, histological grade and specific breast tumor subtypes (12,13 ) and triple-negative tumors (14). Although it is not yet fully understood, these processes may also be reflected in telomere length alteration in peripheral blood leukocytes (15).…”

Section: Introductionmentioning

confidence: 99%

Telomere length assessment in leukocytes presents potential diagnostic value in patients with breast cancer

et al. 2016

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Abstract.Telomere shortening is associated with cancer development, primarily through the induction of genomic instability. The majority of studies have indicated that individuals with shorter blood telomeres may be at a higher risk of developing various types of cancer. There is increasing evidence that the study of the alterations in telomere length may improve cancer prognosis. The aim of the present study was to verify the use of telomere length parameters in the diagnostics of breast cancer stage. Telomere length was analyzed in the blood leukocytes of 52 patients with breast cancer relative to 47 control subjects using quantitative polymerase chain reaction. The effects of stage, grade, estrogen receptor, progesterone receptor and human epidermal growth factor 2 (HER2) status were assessed. The current study demonstrated that the average telomeric sequence length was significantly shorter in leukocytes from individuals diagnosed with a more severe stage of breast cancer (T2N1M0) than in leukocytes in the early stages of the disease (T1N0M0) (P=0.0207). Furthermore, the data indicated that telomeres in leukocytes derived from patients with HER2 + breast cancer were significantly longer compared with those with the HER2 -type (P=0.0347). These results suggest that the assessment of telomeres in blood leukocytes may, at least partially, correspond with breast cancer staging and HER2 receptor status.

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Genetic Anticipation Is Associated with Telomere Shortening in Hereditary Breast Cancer

Cited by 81 publications

References 41 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

Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants

Telomere length assessment in leukocytes presents potential diagnostic value in patients with breast cancer

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