Birth length and weight as predictors of breast cancer prognosis

Background Birth size, and particularly birth length, is positively associated with breast cancer risk in adulthood. The objective of this study was to examine whether birth size is associated with survival among breast cancer patients. Methods Information on birth size (weight, length and ponderal index (kg/length (m3)) was collected from birth archives for 331 breast cancer patients who were diagnosed at two university hospitals in Norway (Bergen and Trondheim). The patients were followed from the time of diagnosis until death from breast cancer, death from another cause, or to the end of follow-up, and birth size was related to survival, using Cox regression analysis. Results Breast cancer patients with birth length ≥ 52 cm had nearly twice the risk of dying (hazard ratio, 1.92, 95% confidence interval, 1.09-3.41) from breast cancer compared to women with birth length less than 48 cm, after adjustment for place of birth and year of diagnosis. Similar analyses related to birth weight and ponderal index showed no clear association with breast cancer survival. Conclusions Poorer outcome of breast cancer patients with high birth length may reflect effects of factors that stimulate longitudinal growth and simultaneously increase the risk of metastases and fatal outcome. It is possible that the insulin-like growth factor (IGF) system is involved in the underlying mechanisms

Pedigrees of the breast cancer cases with germline mutations in <i>CHEK2</i>.

<p>The index individuals initially screened are indicated with arrows. All cancer patients marked in bold, and cancers are indicated by type and age at diagnosis. D followed by number indicates the age of death. #, indicate that diagnosis could not be verified from medical documents. Mut −, indicates individuals tested negative for relevant mutations. Mut +, indicates that individuals hold the relevant mutation. The trees have been altered to preserve anonymity, but the meaning of the report is not affected by these alterations. BC, Breast cancer; BD, Blood disease; BLC, Bladder cancer; CC, Colon cancer; EC, Endometri cancer; GC, Gastric cancer; HD, Heart disease; HL, Hodgkins Lymphoma; L, Lymphoma; LAC, Larynx cancer; LC, Lung cancer; LE, Leukemia; LEC, Liver cancer; OC, Ovarian cancer; OL, Oral Lymphoma M; P, Parkinson; PC, Prostate cancer; SA, Sarcoma; SE, Seminom; SI, Carcinoid in small intestine; TBC, Tuberculosis.</p

Characteristics of <i>CHEK2</i> mutants found and clinical data

<p>¹, The bolded bases indicate the base change; T N M, TNM-classification, AJCC 2002 = UICC 2002, T, size or direct of the primary tumor; N, spread to regional lymph nodes; M, distant metastasis; ³, “F” followed by a number indicates that the patient was free of disease at that number of months of follow-up. “R” followed by a number indicates that the patient was alive at that number of months of follow-up but had suffered a relapse; ˆ, “A” followed by a number indicates that the patient was alive at that number of months of follow-up. “D” followed by a number indicates that the patient died at that number of months of follow-up; AI, Allelic imbalance; NI, Not informative; NA, Not available. “^*” This patient subsequently relapsed with distant metastases at 64 months.</p

Kinase activity of <i>CHEK2</i> mutants.

<p>A) Level of Chk2 mutants immunoprecipitated from U-2-OS cells, used as input for kinase activity assay, monitored by anti-V5 based Western blot analysis. B) Autoradiogram showing <i>in vitro</i> kinase activity of Chk2 mutants with respect to both Chk2 autophosphorylation and Cdc25 phosphorylation. C) Kinase activity of <i>CHEK2</i> mutants normalized for kinase-input, based on band intensities in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003062#pone-0003062-g003" target="_blank">Figures 3A and B</a>.</p

Kaplan-Meyer analysis of the relapse-free survival of the patients according to mutations.

<p>WT, wild-type; <i>TP53</i>+<i>CHEK2</i> mut, all found mutations in <i>TP53</i> and <i>CHEK2</i>; <i>TP53</i> L2/L3+<i>CHEK2</i> (Arg95Ter) mut, <i>TP53</i> mutations affection L2/L3 domain and <i>CHEK2</i> mutations affecting kinase function; <i>TP53</i>+<i>CHEK2</i> (Ile364Thr), mutations not affecting L2/L3 domains and <i>CHEK2</i> mutations not affecting kinase function. Deaths due to causes other than breast cancer are treated as censored observations. Each “+” mark represents the time one patient was censored. NS, Non significant.</p

Pulldown-assay for <i>CHEK2</i> mutants.

<p>V5-tagged Chk2 mutants were co-expressed with Xpr-tagged wt-Chk2 in U-2-OS-cells and immunoprecipitation was performed using anti-V5 antibody. Expression of the Chk2 mutants was monitored by anti-V5 based Western blot analysis prior to immunoprecipitation (upper panel). The Chk2 mutant's ability to dimerize with the wild-type protein was detected by anti-Xpr Western blot analysis of the precipitate (lower panel).</p

PCR primers for amplification and sequencing of cDNA

<p>PCR primers for amplification and sequencing of cDNA</p

Clinical response in relation to different parameters

<p><i>P¹</i> with regard to clinical response comparing CR+PR+SD versus PD</p><p><i>P²</i> with regard to clinical response comparing CR+PR versus PD</p>*<p>One of the PD patients has got a mutation both in <i>CHEK2</i> and <i>TP53</i> (L2 domain), this has been taken into consideration under calculation of statistical significance</p>1<p>P, with regard to clinical response comparing CR+PR versus PD; ²P, with regard to clinical response comparing CR+PR+SD versus PD; ^*, One of the PD patients has got a mutation both in <i>CHEK2</i> and <i>TP53</i> (L2 domain), this has been taken into consideration under calculation of statistical significance.</p