Breast Cancer Survival Is Associated with Telomere Length in Peripheral Blood Cells

Svenson, Ulrika; Nordfjäll, Katarina; Stegmayr, Birgitta; Manjer, Jonas; Nilsson, Peter M.; Tavelin, Björn; Henriksson, Roger; Lenner, Per; Roos, Göran

doi:10.1158/0008-5472.can-07-6497

Cited by 160 publications

(187 citation statements)

References 39 publications

(42 reference statements)

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“…1A) with a similar magnitude of effect as seen in previous comparable studies (4,24). Longer age-adjusted maternal TL predicted longer offspring TL (Fig.…”

Section: Resultssupporting

confidence: 86%

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.

185

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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“…1A) with a similar magnitude of effect as seen in previous comparable studies (4,24). Longer age-adjusted maternal TL predicted longer offspring TL (Fig.…”

Section: Resultssupporting

confidence: 86%

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.

185

170

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“…Recently, Svenson et al 27 showed that telomere length in peripheral blood cells differs between breast cancer patients and control subjects, and may serve as a significant prognostic biological marker. In general, malignant tumors show shorter telomeres than corresponding normal tissue, and telomere dysfunction has been indicated as a negative prognostic marker in solid tumors, including breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Correlation of telomere length shortening with promoter methylation profile of p16/Rb and p53/p21 pathways in breast cancer

et al. 2010

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Unregulated cell growth, a major hallmark of cancer, is coupled with telomere shortening. Measurement of telomere length could provide important information on cell replication and proliferation state in cancer tissues. Telomere shortening and its potential correlation with downregulation of cell-cycle regulatory elements were studied by the examination of relative telomere length and methylation status of the TP53, P21 and P16 promoters in tissues from breast cancer patients. Telomere length was measured in 104 samples (52 tumors and paired adjacent normal breast tissues) by quantitative PCR. Methylation profile of selected genes was analyzed in all samples using a matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Our results demonstrated a significant shortening of tumor telomere regions compared with paired adjacent normal tissues (Po0.001). Similarly, telomere lengths were significantly shorter in advanced stage cases and in those with higher histological grades (Po0.05). Telomere shortening in cancer tissues was correlated with a different level of hypermethylation in the TP53, P21 and P16 promoters (r ¼ À0.33, P ¼ 0.001; r ¼ À0.70, Po0.0001 and r ¼ À0.71, Po0.0001, respectively). The results suggested that inactivation of p16/Rb and/or p53/p21 pathways by hypermethylation may be linked to critical telomere shortening, leading to genome instability and ultimately to malignant transformation. Thus, telomere shortening and promoter hypermethylation of related genes both might serve as breast cancer biomarkers.

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“…[40][41][42][43][44] Short telomeres are not only a by-product of tumor development. In fact, telomeric loss could be instrumental in maximizing the malignant potential of tumor cells by boosting genetic instability and by interfering epigenetically with genes located in subtelomeric regions.…”

Section: Discussionmentioning

confidence: 99%

Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia

et al. 2009

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Breast Cancer Survival Is Associated with Telomere Length in Peripheral Blood Cells

Cited by 160 publications

References 39 publications

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

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

Correlation of telomere length shortening with promoter methylation profile of p16/Rb and p53/p21 pathways in breast cancer

Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia

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