Genetic variation in 8q24 associated with risk of colorectal cancer

Chromosome 8q24 harbors oncogenes known to be involved in pathogenesis of colorectal cancer (CRC) as well as uncharacterized genetic variants that have recently been shown to influence inherited risk of prostate cancer. In a population-based case-control study of colorectal cancer in northern Israel, we investigated the association between variation in 8q24 and risk of CRC. Among 1,861 incident cases and 1,937 population-based controls matched on age, gender, ethnicity, and clinic, rs10505477 was associated with risk of CRC in a dominant model, with an odds ratio = 1.23, 95% confidence interval = 1.05-1.43, (p = 0.008). This association was independently validated in an analysis of cancer among relatives of carriers of the risk allele, with a hazard ratio of 3.2 (95% bootstrap CI = 1.16-17.8). Genetic variation at rs10505477 on 8q24 potentially accounts for 14% of CRC in this population and should be replicated in other studies.     

Association of genetic variants at 8q24 with breast cancer risk.

Recent whole genome association studies of prostate, breast, and colorectal cancer have identified susceptibility loci on 8q24. We genotyped three variants associated with prostate cancer (rs10090154, rs13254738, and rs7000448), one associated with both prostate and colorectal cancer (rs6983267), and one associated with breast cancer (rs13281615) in a series of 1,499 breast cancer cases and 1,390 controls. 1,267 (85%) of the cases had two primary breast cancers. Our analysis provides further evidence of the relationship between rs13281615 and risk of breast cancer, with heterozygote odds ratio (OR) 1.30 95% confidence interval (CI) 1.09-1.54 and homozygote OR 1.52 (95% CI, 1.22-1.89; P trend = 0.00003), and confirms the prediction that the risk is substantially higher in this genetically enriched series (OR per allele, 1.24; 95% CI, 1.12-1.38) than in a large series of mainly unselected cases (reported OR per allele, 1.08; 95% CI, 1.05-1.11). We observed a protective effect of rs13254738 for breast cancer (allelic OR, 0.88; 95% CI, 0.78-0.98; P = 0.02), which is supported by the Cancer Genetic Markers of Susceptibility data (pooled allelic OR, 0.88; 95% CI, 0.81-0.96; P = 0.003). None of the other three single nucleotide polymorphisms, two associated with prostate (rs10090154 and rs7000448) and one with both prostate and colorectal cancers (rs6583267), was associated with breast cancer risk in our study. This evidence of a protective effect for breast cancer of one variant (rs13254738) that has been associated previously with a 1.25-fold increased risk of prostate cancer, with no effect for the two other variants, indicates that the effects of the risk alleles clustered at 8q24 are cancer site specific.     

Polymorphism of 8q24 rsl3281615 and breast cancer risk

Several genome-wide association studies on breast cancer have reported similar findings of a new cancer susceptibility locus, 8q24 rsl3281615. Subsequent case–control studies have rapidly investigated the association between the single nucleotide polymorphism of rsl3281615 at chromosome 8q24 and breast cancer risk, but the effect of 8q24 rsl3281615 polymorphism on breast cancer is still unclear due to the inconsistence among those studies. Given the contradictory findings, a meta-analysis was performed to determine the association between 8q24 rsl3281615 polymorphism and breast cancer risk. 12 eligible case–control studies with a total of 42,508 cases and 53,928 controls were finally included into this meta-analysis by searching the PubMed, Embase, and China Biology Medicine (CBM) databases. We estimated the summary odds ratio (OR) with its corresponding 95 % confidence interval (95 % CI) to assess this association. Meta-analyses of total 12 studies showed 8q24 rsl3281615 polymorphism was significantly associated with an increased risk of breast cancer in all contrast models (OR_{G vs. A}?=?1.10, 95 % CI 1.05–1.14, P _OR?<?0.001; OR_{GG vs. AA}?=?1.20, 95 % CI 1.11–1.29, P _OR?<?0.001; OR_{AG vs. AA}?=?1.08, 95 % CI 1.05–1.12, P _OR?<?0.001; OR_{GG vs. AA +AG}?=?1.13, 95 % CI 1.07–1.19, P _OR?<?0.001; OR_{GG+AG vs. AA}?=?1.13, 95 % CI 1.07–1.19, P _OR?<?0.001). Meta-analyses of studies with high quality showed that 8q24 rsl3281615 polymorphism was still significantly associated with an increased risk of breast cancer under the five genetic contrast models. Sensitivity analyses by sequential omission of any individual studies and subgroup analyses by ethnicity further identified the significant association between 8q24 rsl3281615 polymorphism and breast cancer risk. Conclusively, this meta-analysis shows a significant association between 8q24 rsl3281615 polymorphism and breast cancer risk.     

Confirmation of a positive association between prostate cancer risk and a locus at chromosome 8q24.

BACKGROUND: Family-based linkage studies, association studies, and studies of tumors have highlighted human chromosome 8q as a genomic region of interest for prostate cancer susceptibility loci. Recently, a locus at 8q24, characterized by both a single nucleotide polymorphism (SNP) and a microsatellite marker, was shown to be associated with prostate cancer risk in Icelandic, Swedish, and U.S. samples. Although the data were provocative, the U.S. samples were not population based, which precludes assessment of the potential contribution of this locus to prostate cancer incidence in the United States. METHODS: We analyzed both markers in a population-based, case-control study of middle-aged men from King County, Washington. RESULTS: Overall, there was a significant positive association between the A allele of the SNP rs1447295 and prostate cancer risk [odds ratio, 1.4; 95% confidence interval (95% CI), 1.1-2.0] but no significant association with the microsatellite DG8S737. However, significant associations were observed for both markers in men with high Gleason scores. Adjusting for age, first-degree family history of prostate cancer, and prostate cancer screening history, the adjusted odds ratios were 1.4 (95% CI, 1.1-1.8) for the A allele of the SNP and 1.9 (95% CI, 1.2-2.8) for the -10 allele of the microsatellite. CONCLUSIONS: These data suggest that the locus on chromosome 8q24 harbors a genetic variant associated with prostate cancer and that the microsatellite marker is a stronger risk factor for aggressive prostate cancers defined by poorly differentiated tumor morphology.     

Chromosome 8q24 markers: risk of early-onset and familial prostate cancer

Recent admixture mapping and linkage/association studies have implicated an approximately 1 Mb region on chromosome 8q24 in prostate cancer susceptibility. In a subsequent follow-up investigation, Haiman et al. (Nat Genet 2007;39:638-44) observed significant, independent associations between 7 markers within this region and sporadic prostate cancer risk in a multi-ethnic sample. To clarify the risk associated with hereditary prostate cancer, we tested for prostate cancer association with 6 of these 7 markers in a sample of 1,015 non-Hispanic white men with and without prostate cancer from 403 familial and early-onset prostate cancer families. Single nucleotide polymorphisms (SNPs) rs6983561 and rs6983267 showed the strongest evidence of prostate cancer association. Using a family-based association test, the minor ("C") allele of rs6983561 and the major ("G") allele of rs6983267 were preferentially transmitted to affected men (p < 0.05), with estimated odds ratios (ORs) of 2.26 (95% confidence interval of 1.06-4.83) and 1.30 (95% confidence interval of 0.99-1.71), respectively, for an additive model. Notably, rs6983561 was significantly associated with prostate cancer among men diagnosed at an early (<50 years) but not later age (p = 0.03 versus p = 0.21). Similarly, the association with rs6983267 was (not) statistically significant among men with(out) clinically aggressive disease (p = 0.007 versus p = 0.34). Our results confirm the association of prostate cancer with several of the SNPs on chromosome 8q24 initially reported by Haiman et al. In addition, our results suggest that the increased risk associated with these SNPs is approximately doubled in individuals predisposed to develop early onset or clinically aggressive disease.     

Genetic variation at 8q24, family history of cancer,and upper gastrointestinal cancers in a Chinese population

Genetic variation at 8q24 is associated with prostate, bladder, breast, colorectal, thyroid, lung, ovarian, UADT, liver and stomach cancers. However, a role for variation at 8q24 in familial clustering of upper gastrointestinal cancers has not been studied. In order to explore potential inherited susceptibility, we analyzed epidemiologic data from a population-based case–control study of upper gastrointestinal cancers from Taixing, China. The study population includes 204 liver, 206 stomach, and 218 esophageal cancer cases and 415 controls. Associations between 8q24 rs1447295, rs16901979, rs6983267 and these cancers were stratified by family history of cancer. Odds ratios and 95 % confidence intervals were adjusted for potential confounders: age, sex, education, tobacco smoking, alcohol consumption, and BMI at interview. We also adjusted for hepatitis B and aflatoxin (liver cancer) and Helicobacter pylori (stomach cancer). In a dominant model, among those with a family history of cancer, rs1447295 was positively associated with liver cancer (OR_adj 2.80; 95 % CI 1.15–6.80). Heterogeneity was observed (P _{heterogeneity} = 0.029) with rs6983267 and liver cancer, with positive association in the dominant model among those with a family history of cancer and positive association in the recessive model among those without a family history of cancer. When considered in a genetic risk score model, each additional 8q24 risk genotype increased the odds of liver cancer by two-fold among those with a family history of cancer (OR_adj 2.00; 95 % CI 1.15–3.47). These findings suggest that inherited susceptibility to liver cancer may exist in the Taixing population and that variation at 8q24 might be a genetic component of that inherited susceptibility.     

A common 8q24 variant and the risk of colon cancer: a population-based case-control study.

Three recent studies identified common variants on 8q24 that confer modestly increased susceptibility to colorectal cancer. Here, we replicate the association in a population-based case-control study of colon cancer, including 561 cases and 721 unrelated controls. The rs6983267 marker was significantly associated with colon cancer risk. Compared with those homozygous for the T allele, the heterozygous and homozygous carriers for the G allele had an age-adjusted odds ratio of 1.39 (95% confidence interval, 1.03-1.88) and 1.68 (95% confidence interval, 1.21-2.33), respectively. An additive model showed strong evidence for a gene-dose response relationship (P(trend) = 0.0022). The association remained statistically significant when restricted to Caucasians only (527 cases and 679 controls; P(trend) = 0.0056). Further adjustment for other known risk factors did not alter the results. Stratified analysis revealed no evidence for effect modification by family history of colorectal cancer, age, or gender. These data replicate the association identified from recent studies, providing additional evidence supporting the rs6983267 genetic polymorphism as a marker predisposing to colon cancer.     

Multiple independent genetic variants in the 8q24 region are associated with prostate cancer risk.

Recently, the 8q24 region has been identified as a prostate cancer susceptibility locus in a genome-wide scan of prostate cancer families in Iceland and an admixture scan of African Americans. Further investigations of variants at 8q24 have shown the existence of additional single nucleotide polymorphisms (SNPs) that enhance prostate cancer risk, suggesting the possibility of multiple regions harboring variants for the disease. In the present population-based study of Caucasians (1,308 cases and 1,266 controls) and African Americans (149 cases and 85 controls), we tested the association between prostate cancer and 23 SNPs in the 8q24 region. Fourteen SNPs in Caucasians and 5 SNPs in African Americans were significantly associated with risk of prostate cancer after adjusting for multiple comparisons; of these, 5 SNPs in Caucasians and 3 in African Americans were independently associated with risk. The strongest association was for rs6983561 (carriers of any C allele) with an odds ratio of 1.6 (95% confidence interval, 1.1-2.1) in Caucasians; variants in rs979200, rs1016343, rs7837328, and rs10090154 were also independently associated with risk. In African Americans, the strongest association was for rs7000448 (carriers of any T allele) with an odds ratio of 3.4 (95% confidence interval, 1.3-8.7). In addition, two SNPs that extend the boundaries of the 8q24 region were significantly associated with risk: rs979200 at the centromeric boundary and rs3891248, located in the first intron of the c-MYC gene (IVS1-355), which identifies a new telomeric boundary.     

Two common chromosome 8q24 variants are associated with increased risk for prostate cancer

Two variants (rs1447295/DG8S737) of chromosome 8q24 were recently reported to be associated with increased risk of prostate cancer (PC). To confirm this finding, we genotyped and compared the frequencies of these polymorphisms among 1,121 Caucasian men with PC (435 men with familial PC, 491 men with sporadic PC, and 195 men with aggressive PC) to 545 population-based controls. For the single nucleotide polymorphism marker rs1447295, frequencies of the minor allele (A) were 10.3% in controls, 11.9% in sporadic cases, 16.7% in familial cases, and 17.2% in aggressive cases. Compared with controls, the A allele was significantly more common in both familial PC [odds ratios (OR), 1.93; 95% confidence intervals (95% CI), 1.37-2.72; P = 0.0004] and aggressive PC (OR, 1.87; 95% CI, 1.28-2.74; P = 0.0005) but not for sporadic PC (OR, 1.16; 95% CI, 0.85-1.58; P = 0.25). Although the A allele was more frequent in aggressive PC cases when compared with controls, the allele frequencies were similar among cases with high- and low-grade PC (Gleason grades <7 and >/=7, respectively). For the microsatellite marker DG8S737, the -8 allele was significantly more frequent in familial PC (OR, 1.68; 95% CI, 1.09-2.60; P = 0.031), whereas the -10 allele was more frequent in aggressive PC (OR, 2.85; 95% CI, 1.52-5.36; P = 0.0004). Haplotype analysis showed significant differences in haplotype frequencies between the familial PC (P = 0.006) and aggressive PC (P = 0.005) cases versus controls. The -8/A haplotype showed the strongest association with familial PC (P = 0.008), whereas the -10/A haplotype was most strongly associated with aggressive PC (P = 0.00005). These results further confirm the importance of these two polymorphic variants (rs1447295 and DG8S737) as risk factors for PC. However, the mechanism explaining this increased risk has not yet been established.     

Common 8q24 sequence variations are associated with Asian Indian advanced prostate cancer risk

Three sequence variations (rs1447295, rs16901979, and rs6983267) on 8q24 were recently shown to independently affect prostate cancer risk. Asian Indians have a low prostate cancer risk; however, in the absence of screening practices for the disease, most are diagnosed with metastatic prostate cancer. We evaluated the association of these single nucleotide polymorphisms (SNP) with advanced prostate cancer in 153 prostate cancer cases and 227 age-matched controls (northern India). Overall, there was a positive association between carriers of the allele A of rs1447295 and prostate cancer risk [odds ratio (OR), 1.60; 95% confidence interval (95% CI), 1.01-2.52] but no significant association with carriers of alleles A of rs16901979 and allele G of rs6983267. However, significant associations were observed for both SNPs in men with high Gleason scores (>/=7) and metastasis. Adjusting for age, the ORs were 1.77 (95% CI, 1.05-2.97) for carriers of rs1447295 A and 1.85 (95% CI, 1.04-3.28) for carriers of the rs16901979 A allele. We also observed significant joint effects among these loci associated with prostate cancer risk and severity, suggestive of additive effects of the independent SNPs. The ORs for the combined effects of rs1447295 A with rs16901979 A or rs6983267 G were 2.61 (95% CI, 1.11-6.12) and 1.84 (95% CI, 1.12-3.06), respectively. There was no joint effect between SNPs rs16901979 A and rs6983267 G. These results confirm the significance of these SNPs in prostate cancer etiology in a previously unstudied population who do not undergo prostate cancer screening and are diagnosed with severe disease.     

Common variation rs6983267 at 8q24.1 and risk of colorectal adenoma and cancer: evidence based on 31 studies

Genome-wide association studies have identified 8q24.21-rs6983267 as a new colorectal cancer (CRC) and colorectal adenoma (CRA) susceptibility locus in populations of European descent. Since then, the relationship between 8q24.21-rs6983267 and CRC/CRA has been reported in various ethnic groups; however, these studies have yielded inconsistent results. To investigate this inconsistency and derive a more precise estimation of the relationship, we conducted a meta-analysis of 31 studies, including 51,293 cases and 58,962 controls for CRC, and 8,148 cases and 17,065 controls for CRA. Potential sources of heterogeneity and publication bias were also systematically explored. Overall, the summary odds ratio of G variant for CRC was 1.18 (95 % CI, 1.16–1.21; P?<?10^?5) and 1.17 (95 % CI, 1.11–1.23; P?<?10^?5) for CRA. Significant results were observed using dominant or recessive genetic model for the polymorphism. In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians and Caucasian populations; while no significant associations were detected among African Americans. After stratifying by sample size and control source, significant associations were also obtained. This meta-analysis suggests that the 8q24.21-rs6983267 polymorphism is associated with CRC/CRA susceptibility, but these associations vary in different ethnic populations.     

Organochlorines and endometrial cancer risk.

There is concern that persistent environmental pollutants such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) increase breast cancer risk, at least partially through estrogenic effects. Because the endometrium is more sensitive to estrogenic stimulation than the breast, such a carcinogenic effect should be more pronounced in the endometrium than the breast. In a population-based case-control study in Sweden, we measured serum concentrations of 10 chlorinated pesticides and 10 PCB congeners in 154 endometrial cancer cases and 205 population controls. Information on potential confounders was obtained by mailed questionnaires. We used logistic regression to calculate odds ratios (ORs) as measures of relative risk. We performed analyses for lipid-adjusted concentrations of each individual substance and after grouping substances according to putative hormonal effects. We found no significant associations of increasing levels of pesticide or PCB exposure with endometrial cancer risk. The multivariate OR was 1.0 (95% confidence interval, 0.6-2.0; P for trend, 0.78) for the highest compared with the lowest quartile of dichlorodiphenyldichloroethylene (DDE), the predominant dichlorodiphenyltrichloroethane metabolite. Corresponding ORs were 1.0 for hexachlorobenzene, 0.9 for beta-hexachlorocyclohexane, 1.4 for oxychlordane, and 1.2 for trans-nonachlor. Analyses of substances grouped by putative hormonal effect also showed no associations with endometrial cancer risk. For all estrogenic compounds, the OR for the highest compared with the lowest quartile was 1.1 (95% confidence interval, 0.6-2.2; P for trend, 0.90). Our data do not support the hypothesis that the organochlorine exposure studied increases the risk for endometrial cancer.     

Body mass at different ages and subsequent endometrial cancer risk.

The relationship between body mass index (BMI) at different ages and subsequent endometrial-cancer risk was investigated in a multicentre case-control study conducted between 1988 and 1991 in Vaud, Switzerland, and Northern Italy on 272 histologically confirmed incident cases of endometrial cancer and 571 controls admitted to hospital for acute, non-neoplastic conditions, unrelated to known or potential risk factors for endometrial cancer. The risk of endometrial cancer increased with increasing BMI in the 3rd decade of age (20 to 29 years), in the 5th decade (40 to 49 years) and in the 7th decade (60 to 69 years), although the risk estimates tended to be substantially higher at older ages: compared with women whose BMI (kg m-2) was less than 20, the relative risks (RR) were 1.8 for BMI greater than or equal to 25 at age 20 to 29, 2.7 for BMI greater than or equal to 30 at age 40 to 49 and 3.8 at age 60 to 69. All the trends in risk were significant, except that for BMI at age 25 after allowance for current BMI. When data were examined in separate strata of current BMI, among women of normal body mass at diagnosis no significant effect of past overweight was observed. In contrast, among subjects over-weight at diagnosis, there were significant direct relationships with BMI at ages 20 to 29 and 40 to 49. To reduce endometrial cancer risk, it is therefore important to avoid obesity in later middle and older age, and the benefit can be even greater for women who were overweight at younger age.     

Association between polymorphisms in long non-coding RNA PRNCR1 in 8q24 and risk of colorectal cancer

Background

Genome-wide association studies have identified that genetic variants in 8q24 confer susceptibility to colorectal cancer (CRC). Recently, a novel lncRNA (PRNCR1) that located in the 8q24 was discovered. Single nucleotide polymorphisms (SNPs) in the lncRNAs may influence the process of splicing and stability of mRNA conformation, resulting in the modification of its interacting partners. We hypothesized that SNPs in the lncRNA PRNCR1 may be related to the risk of CRC.

Methods

We conducted a case–control study and genotyped five tag SNPs in the lncRNA PRNCR1 in 908 subjects including 313 cases with CRC and 595 control subjects using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay.

Results

In overall analyses, we found that the rs13252298 and rs1456315 were associated with significantly decreased risks of CRC. In stratification analyses, we found that CRC patients carrying the rs1456315G were likely to have a tumor size of greater than 5 cm (G vs. A: adjusted OR = 1.56, 95% CI: 1.10-2.23). Additionally, patients with the rs7007694C and rs16901946G had decreased risks to develop poorly differentiated CRC, whereas patients with the rs1456315G had an increased risk to develop poorly differentiated CRC.

Conclusion

These findings suggest that SNPs in the lncRNA PRNCR1 may contribute to susceptibility to CRC.     

染色体8q24区域异常在乳腺癌中的研究进展

近年来基因芯片、高通量测序技术,大规模发现基因组拷贝数变异和单核苷酸多态性等异常改变,其中8号染色体长臂2区4带（8q24）的高频变异在乳腺癌发生发展中的意义日益受到关注。8q24区域包含MYC、PSCA等癌基因和乳腺癌相关风险位点,在乳腺癌中该区域高频扩增与乳腺癌的发生发展及预后密切相关。本文将对乳腺癌中8q24区域的扩增及相关风险位点的特征及乳腺癌相关基因的作用进行综述。      

ASAP1, a gene at 8q24, is associated with prostate cancer metastasis

Metastatic prostate cancer is a terminal disease, and the development of reliable prognostic tools and more effective therapy is critically important for improved disease survival and management. This study was aimed at identifying genes that are differentially expressed in metastatic and nonmetastatic prostate cancer cells and, as such, could be critical in the development of metastasis. Long-SAGE analysis was used to compare a transplantable human metastatic prostate cancer subline, PCa1-met, with a nonmetastatic counterpart, PCa2. Both sublines were developed from a patient's prostate cancer specimen via subrenal capsule grafting and subsequent orthotopic implantation into SCID mice. Among various differentially expressed genes identified, ASAP1, an 8q24 gene encoding an ADP-ribosylation factor GTPase-activating protein not previously associated with prostate cancer, was up-regulated in the metastatic subline as confirmed by quantitative real-time PCR. Immunohistochemistry of xenograft sections showed that cytoplasmic ASAP1 protein staining was absent or weak in benign tissue, significantly stronger in nonmetastatic PCa2 tissue, and strongest in PCa1-met tissue. In clinical specimens, ASAP1 protein staining was elevated in 80% of primary prostate cancers and substantially higher in metastatic lesions compared with benign prostate tissue. Moreover, additional ASAP1 gene copies were detected in 58% of the primary prostate cancer specimens. Small interfering RNA-induced reduction of ASAP1 protein expression markedly suppressed in vitro PC-3 cell migration (approximately 50%) and Matrigel invasion (approximately 67%). This study suggests that the ASAP1 gene plays a role in prostate cancer metastasis and may represent a therapeutic target and/or biomarker for metastatic disease.     

Alcoholism and risk for endometrial cancer.

Endogenous estrogens increase the risk of endometrial cancer and are also elevated among women with high alcoholic intake. It is incompletely known, however, whether alcohol intake in general and alcohol abuse in particular increases risk for endometrial cancer. We thus analyzed prospectively the risk for endometrial cancer among 36,856 women hospitalized with alcoholism between 1965 and 1994 through linkages between several national Swedish registers. Compared with the general population, women who were alcoholics had an overall 24% lower risk of developing endometrial cancer, a finding challenging our a priori hypothesis. However, among women below the age of 50 years at follow-up, the mean age of menopause among Swedish women, the risk was 70% higher, whereas the risk among women aged 50 years or more at follow-up was 40% lower compared with the general population. Hence, the effect of alcoholism on endometrial cancer appears to be age dependent.     

Anthropometric measures at different ages and endometrial cancer risk

Background:

Endometrial cancer is strongly associated with body mass index (BMI), but the influence of BMI history and of different types of obesity is uncertain.

Ethods:

M A case–control study was carried out in Italy including 454 cases and 908 controls admitted to hospital for acute non-hormone-related conditions. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using multivariate logistic and spline regression models.

Results:

The OR for BMI >30 at diagnosis compared with 20 to <25 kg m⁻² was 4.08 (95% CI: 2.90–5.74). The association for BMI was monotonic with a possible steeper increase for BMI above 28. Conversely, waist-to-hip ratio (WHR) showed a bell shaped curve with increased OR (2.10; 95% CI: 1.43–3.09) in the intermediate tertile only. After stratification by BMI at diagnosis, history of weight loss and BMI at age 30 did not influence endometrial cancer risk. History of obesity in middle age had a weak and not significant adverse effect among obese women (OR=1.60; 95% CI: 0.52–4.96).

Conclusion:

The predominant importance of recent weight compared to lifetime history, justifies encouraging weight reduction in women at any age.