Second to Fourth Digit Ratio: Its Relationship with Core Cancer Volume and Gleason Score in Prostate Biopsy

ABStRAct ARtIcLe INfO


INTROdUCTION
The ratio of the 2nd to 4th digit length (digit ratio) of the right hand is known to be fixed in utero (1)(2)(3), and is sexually dimorphic and lower in men than in women (4)(5)(6).The digit ratio is negatively related to prenatal testosterone and positively related to prenatal estrogen concentrations (7).
The digit ratio of the right hand is related to the activity of the androgen receptor (AR) (8).Manning and colleagues demonstrated that the digit ratio of the right-hand is positively cor-related with the CAG repeat number of the AR gene, and that individuals with a low digit ratio possess AR alleles with low CAG repeat numbers (8).It has been well established that a low AR CAG repeat number increases the risks of prostate cancer (9,10).
It has recently been suggested that the digit ratio is related to prostate specific antigen (PSA) level and the prostate cancer risk (11).
Based on the above-mentioned evidence, we thought that if digit ratio is related to the prostate cancer risk, digit ratio might be related to the detection rate of prostate biopsies and the biopsy findings including the indices of tumor volume (i.e., the number of cores involved and the percentage of cores involved) and Gleason score.We investigated the relationship between digit ratio and prostate cancer detection rate and biopsy findings.

MATERIALS ANd METHOdS
Among the men that presented with lower urinary tract symptoms (LUTS) at a single tertiary academic center, 770 consecutive men aged 40 years or older were prospectively enrolled.All patients in the present study come from a same ethnic Korean group.
Right hand 2nd and 4th digit lengths were measured by an investigator prior to the PSA determinations and digit rectal examination (DRE) and transrectal ultrasonography (TRUS).The digit lengths were measured directly on the ventral surface of the fingers using a digital vernier calliper (6); this measurement has been previously reported to provide a high degree of repeatability (12,13).To minimize measurement errors, the mean values of duplicate measurements were used in the analysis.
Among 770 men, 166 men with a PSA level ≥ 3 ng/mL or abnormal DRE findings underwent a 12 core prostate biopsy as an initial biopsy.Biopsies were performed transrectally using an 18-gauge biopsy needle and a biopsy gun under TRUS guidance to provide the 17 mm long tissue cores.
The study subjects were allocated into two groups by digit ratio.As noted in previous study (11), we chose 0.95 as the cut-off value because the mean and median values of digit ratio of all patients (n = 770) were 0.948 and 0.946.
The cancer detection rates and biopsy findings were analyzed according to digit ratio.Student's t-test and Chi-square test were used to compare the variables of the two study groups, which were divided by digit ratio.To identify the independent predictive factors influencing prostate cancer detection, univariate and multivariate analysis were performed using logistic regression model.The analysis was performed using SPSS 12.0 (SPSS, Chicago, IL), and differences were considered statistically significant when the P values were less than 0.05.
We analyzed the 408 positive biopsy cores (group A: digit ratio < 0.95, n = 282; group B:

dISCUSSION
In humans, the growth and pattern of digits and the differentiation of gonads are controlled by the homeobox genes HOXA and HOXD (2,13,14).Therefore, gonadal fetal products such as testosterone may influence finger morphology (6,15,16).For example, a high concentration of testosterone, indicating high prenatal testicular activity leads to low digit ratio (17).Recently, Lutchmaya et al. (7) showed that digit ratio is negatively associated with prenatal testosterone levels and it is positively associated with prenatal estrogen levels.
It is well known that testosterone and androgen receptors (AR) play central roles in prostate growth and the development of prostate cancer.The short CAG repeat length of the androgen receptor gene (AR) has been reported to be associated with the aetiologies of prostate cancer (9,10).Manning et al. (8) showed that the right-hand digit ratio is positively correlated with the CAG repeat number of AR.
Recently, Rahman et al. (18) reported that digit ratio is a reasonable marker for evaluation of prostate cancer risk.In their large casecontrol study, a higher digit ratio is related to more protective effect on prostate cancer risk, in particular, patients with age under 60 years.Considering these studies, it is highly suggestive that digit ratio may be related to prostate cancer.
In other study of the relationship between digit ratio and prostate cancer, Jung et al. (11) proposed that the 2nd to 4th digit ratio (digit ratio) of the right hand is related to PSA level and the presence of prostate cancer.They showed the significant negative relationships between digit ratio and PSA level and the presence of prostate cancer.However, Jung et al. (11) did not find that the prostate biopsy findings were correlated to digit ratio because the number of prostate cancer patients in their study was not sufficient to reveal the relationship of digit ratio to the biopsy findings.The histologic grade is the most important piece of information obtained from the needle biopsy.The Gleason grading system is the most commonly used classification scheme for the histologic grading of prostate cancer (19,20).Gleason grade has been shown to correlate with the pathologic extent of disease (21)(22)(23)(24)(25).The presence of a Gleason pattern 4 or greater or a Gleason sum of 7 or greater is particularly predictive of a poorer prognosis.Numerous multi-variate analyses support the assertion that Gleason sum is a strong predictor of the extent of prostate disease (22,23,(26)(27)(28).
According to our data, only five patients had family history of prostate cancer (first-degree relative).At present, the screening of prostate cancer in Korea is not as widespread as in Western countries (29).Furthermore, among Korean men, prostate cancer accounts for 2.4% and 1.5% of the total cancer cases and deaths, respectively (30,31).Also, age-adjusted incidence and mortality rates of prostate cancer in Korea are much lower than those in most Western nations (32).Therefore, it is unusual that the prostate biopsy patients have family history of prostate cancer.
In the present study, besides age, PSA and DRE, univariate and multivariate analysis using logistic regression model showed that digit ratio is also an independent predictor of prostate can- cer detection (Table -2).Therefore, it can be suggested that digit ratio is associated with prostate cancer risk.One of the novel findings of this study was that digit ratio is related to the cancer detection rate and the aggressiveness (high percentage of core cancer volume and high Gleason score) of prostate cancer.To date, only three studies have investigated the relationship between digit ratio and prostate cancer risk (11,18,33).Two studies have reported a strong association between 2D:4D and risk of prostate cancer (11,18).In the other study, although it is weak, an inverse association was observed between 2D:4D and risk of prostate cancer for patients aged < 60 (33).However, these studies did not reveal the relationship between digit ratio and cancer detection rate and cancer aggressiveness.
In other words, most of the positive cores with sum of Gleason score ≥ 9 or all the positive cores with primary Gleason score = 5 were found in the group with a lower digit ratio rather than in the group with a higher digit ratio.These results suggest that digit ratio may predict the histologic grade as well as the cancer detection rate on prostate biopsy.We think that this is very important and it can be highly suggestive of the relationship between digit ratio and cancer aggressiveness.
According to our data, we have found that the prostate biopsy findings of each cancer patient were not related to digit ratio (Table -4).Actually, the total number of patients who had prostate cancer was 61.So, we think that the number of prostate cancer patients was not sufficient to reveal the relationship of digit ratio to the biopsy findings of the patients.However, when we considered the prostate biopsy findings of each positive core, the prostate biopsy findings of the positive cores were related to digit ratio (Tables 5 and 6).Since the total number of positive cores was 408, we think that this number is sufficient to reveal the relationship of digit ratio to the biopsy findings.
Our results show that the positive cores of the patients with a lower digit ratio have a higher percentage of core cancer volume and that a significantly greater proportion of cores with a lower digit ratio have a high Gleason score.Concluding, digit ratio may be related to the histologic grading of prostate cancer and the extent of disease.
Digit ratio is reflective of prenatal androgen exposure and the in utero milieu.Our results show that digit ratio is related to prostate cancer, like was shown by the study of Jung et al. (11).This can be one of the evidences that prenatal androgen exposure (the in utero milieu) may be related to the later development of prostate cancer, which was already proposed by Henderson et al. (34) in 1988.

CONCLUSIONS
Our results showed that a lower digit ratio is related to an increasing probability of detection of prostate cancer, a high percentage of core cancer volume and a high Gleason score.These findings mean that patients with a lower digit ratio have a higher chance of developing prostate cancer and they might have more aggressive prostate cancer.

CONFLICT OF INTEREST
None declared.

Table 5
the sum of Gleason scores ≥ 7, the distributions of sum of Gleason scores as well as primary Gleason score were different between the two groups (Table-6).

Table 3 -Comparison of the study variables between the two studied groups.
digit ratio = 2nd digit length / 4th digit length; PV = prostate volume; PSA = prostate specific antigen; dRE = digital rectal examination.

Table 4 -Comparison of the study variables between the two studied groups.
digit ratio = 2nd digit length / 4th digit length; PV = prostate volume; PSA = prostate specific antigen; PSAd = prostate specific antigen density; GS = Gleason score.

Table 6 -Comparison of the positive cores with GS ≥ 7 between the two studied groups.
% = percentage; Digit ratio = 2nd digit length / 4th digit length; GS = Gleason score.