DNA Methylation Markers in Lung Cancer

Lung cancer is the most common cancer and the leading cause of cancer-related morbidity and mortality worldwide. As early symptoms of lung cancer are minimal and non-specific, many patients are diagnosed at an advanced stage. Despite a concerted effort to diagnose lung cancer early, no biomarkers that can be used for lung cancer screening and prognosis prediction have been established so far. As global DNA demethylation and gene-specific promoter DNA methylation are present in lung cancer, DNA methylation biomarkers have become a major area of research as potential alternative diagnostic methods to detect lung cancer at an early stage. This review summarizes the emerging DNA methylation changes in lung cancer tumorigenesis, focusing on biomarkers for early detection and their potential clinical applications in lung cancer.     

Socioeconomic Disparity in Breast Cancer Detection in Hong Kong – A High Income City: Retrospective Epidemiological Study Using the Breast Cancer Registry

Background

It is not known whether socioeconomic disparities affect the detection of breast cancer in Asian countries where the incidence of breast cancer is a rising trend. In this study, we explore the socioeconomic profiles of women and the stage of the disease at the time of diagnosis in breast cancer patients aged 40 or over in Hong Kong.

Method

During the period 2008 to 2011, 5393 breast cancer patients registered with the Hong Kong Breast Cancer Registry. Participants and their clinicians were asked to complete standardised questionnaires including patient socio-demographics, health history and risk factors, the course of the disease, post-treatment physical discomfort and psychosocial impact, follow-up recurrence and survival status.

Results

Monthly household incomes, educational levels and the practice of regular screening are independently associated with the stage of the disease at diagnosis. Higher socioeconomic status and a higher educational level were associated with an earlier stage of the disease at the time of diagnosis. Yearly clinical examinations, ultrasound and mammographic screening every 2 to 3 years were significantly associated with the earlier detection of breast cancer.

Conclusion

There were socioeconomic disparities among Hong Kong women who were found to have breast cancer. Population-based screening policies, including raising awareness among women at risk, should be implemented.     

Sputum analysis: Non‐invasive early lung cancer detection

Lung cancer is the leading cause of cancer‐related deaths over the world, characterized by a very high mortality rate. Molecular technique development tries to focus on early detection of cancers by studying molecular alterations that characterize cancer cells. Worldwide lung cancer research has focused on an ever‐increasing number of molecular elements of carcinogenesis at genetic, epigenetic and protein levels. The non‐invasiveness is the characteristic that all clinical trials on cancer detection should have. Abnormal chest imaging and/or non‐specific symptoms are initial signals of lung cancer that appear in an advanced stage of disease. This fact represents the cause of the low 5‐year survival rate: over 90% of patients dying within 5 years of diagnosis. Since smokers have higher quantity of sputum containing exfoliated cells from the bronchial tree, and the sputum represents the most easily accessible biological fluid and its collection is non‐invasive, analysis of this sample represents a good area of research in early lung cancer diagnosis. Continued cigarette smoking is the cause of chronic obstructive pulmonary disease (COPD), with an estimated attributable risk factor exceeding 80% in smoking affected individuals. Lung cancer is found in 40–70% of patients with COPD, particularly in severe disease, and it is a common cause of death in these patients. A large prospective trial of almost half a million non‐smokers showed as lung cancer is also common in patients with COPD who have never smoked. This review describes issues related to early lung cancer screening using non‐invasive methods. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.     

Carcinoma of the Colon and Rectum: A Perspective for Practicing Physicians,with Recommendations for Screening

Carcinoma of the colon and rectum is the most common serious type of cancer found in the United States and is second only to lung cancer among causes of death from cancer. Its cause is unknown but several environmental factors—especially low bulk, high fat diets—seem to predispose to its development. The disease is readily treatable by surgical operation if it is diagnosed early. Radiation and chemotherapy may offer some additional benefit in treating advanced disease but the response to all forms of therapy is disappointing in patients in whom disease has spread beyond the bowel wall. Colorectal cancer appears to be a very slowly progressive disease with a long asymptomatic period providing an ideal opportunity for diagnosis at an early treatable stage. Both proctosigmoidoscopy and screening specimens of stool for occult blood have been shown to be effective methods for identifying it before symptoms develop. These procedures should be done routinely in all patients over 40 years old and especially in those patients who have other risk factors such as positive family histories or hereditary conditions known to predispose to colorectal cancer.     

On the optimal policies of cancer screening.

Some problems of optimal screening are considered. A screening strategy is allowed to be nonperiodic. Two approaches to screening optimization are used: the minimum delay time approach and the minimum cost approach. Both approaches are applied to the analysis of an optimization problem when the natural history of the disease is known and when it is unknown (a minimax problem). The structure of optimal screening policies is investigated as well as the benefit they can provide compared to the periodic screening policy. The detection probability is assumed to depend only on the stage of the disease, though it may not be constant throughout each stage. It is shown that periodic screening appears to be optimal when one has no information on the natural history of the disease, the minimum delay time criterion being used for optimization. Some applications to lung cancer screening are presented.     

Serum-based protein biomarkers for detection of lung cancer

Lung cancer is one of the most common cancers in terms of both incidence and mortality.The major reasons for the increasing number of deaths from lung cancer are late detection and lack of effective therapies. To improve our understanding of lung cancer biology, there is urgent need for blood-based, non-invasive molecular tests to assist in its detection in a cost-effective manner at an early stage when curative interventions are still possible. Recent advances in proteomic technology have provided extensive, high throughput analytical tools for identification, characterization and functional studies of proteomes. Changes in protein expression patterns in response to stimuli can serve as indicators or biomarkers of biological and pathological processes as well as physiological and pharmacological responses to drug treatment, thus aiding in early diagnosis and prognosis of disease. However, only a few biomarkers have been approved by the FDA to date for screening and diagnostic purposes. This review provides a brief overview of currently available proteomic techniques, their applications and limitations and the current state of knowledge about important serum biomarkers in lung cancer and their potential value as prognostic and diagnostic tools.     

Stage at diagnosis and mortality in patients with adenocarcinoma and adenosquamous carcinoma of the uterine cervix diagnosed as a consequence of cytologic screening

OBJECTIVE: To determine if cytologic screening is associated with early stage at diagnosis of and decreased mortality from invasive adenocarcinoma and adenosquamous carcinoma of the uterine cervix. STUDY DESIGN: We retrospectively reviewed the medical records of all 169 women diagnosed with invasive adenocarcinoma or adenosquamous carcinoma of the cervix in a prepaid health plan during 1988-1994. Differences in stage and survival were assessed in relation to screening history and symptoms. RESULTS: Among the 169 cases, late-stage disease was present in 19/169 women (11.2%) at the time of diagnosis, and 24/269 (14.2%) women died of the disease during the three-year follow-up period. Women whose cancer was screen detected numbered 48/169 (28.4%) and were less likely to present with late-stage disease than non-screen-detected women: 2/48 (4.2%) versus 17/121 (14.0%) (P = .05). A mortality advantage at three years from diagnosis was associated with screen-detected cancers: 1/48 (2.1%) versus 23/121 (19.0%) (P = .002), and this advantage persisted after controlling for stage at diagnosis. CONCLUSION: Invasive adenocarcinomas and adenosquamous carcinomas of the cervix detected by screening are found at an earlier stage and are associated with lower disease-specific mortality than those not detected by screening.     

The role of CA 125 in screening for ovarian cancer

Ovarian cancer has the worst prognosis of any gynaecological malignancy, primarily because it tends to present at an advanced stage. The excellent survival rates of early stage disease have provided the rationale for efforts to detect ovarian cancer early by screening, in the hope that survival rates will be improved. Available data suggests that CA 125 is elevated in the majority of epithelial ovarian malignancies prior to clinical presentation. Large trials of screening for ovarian cancer indicate that using a CA 125 cutoff value of 30 U/mL has good sensitivity, but inadequate specificity for detecting preclinical disease. Use of transvaginal ultrasonography as a second-line test in women with elevated CA 125 levels improves specificity to acceptable levels, as does use of a mathematical algorithm which analyses rates of change of CA 125. Two major randomised controlled trials, investigating the effect of screening strategies incorporating CA 125 on mortality, are currently underway.     

Lung cancer proteomics,clinical and technological considerations

The overall survival of lung cancer patients is disappointingly low. This is due to several factors, including the lack of an effective screening strategy to detect tumors at a potentially curable early stage, a marked resistance of lung cancer cells to drug treatment and a still superficial knowledge about the multifactorial cellular networks that are activated or suppressed during cancer progression. Furthermore, the armamentarium of clinicians and researchers in the field does not yet include reliable biomarkers to predict tumor response to treatment and foresee the natural history of the disease. In the present situation, a potential breakthrough is presented by proteomics technologies with the potential to discover relevant biomarkers which can be accurately quantified in multiplexed assays. Proteomics field can also contribute greatly in the understanding of mechanisms in tumor progression and treatment response.     

Bilateral breast cancer in northern Alberta: risk factors and survival patterns.

Of 2231 women with stage I, II or III breast cancer who were registered and seen between 1971 and 1979 and followed to the end of 1981, 48 (2.2%) had synchronous and 58 (2.6%) asynchronous bilateral breast cancer. The unadjusted incidence rate for a second breast cancer was 6.4/1000 breast-years at risk, compared with a rate of 0.70 for the risk of a first breast cancer in women. When calculated from the date of diagnosis of the first breast cancer the survival rate was better for the group with asynchronous disease than for the group with synchronous disease or for a group with unilateral disease, but when calculated from the date of diagnosis of the second cancer the rate was the same in all three groups. Comparison of known risk factors showed a significant association between the development of bilateral cancer and a later age at the birth of the first child and a longer interval between menarche and that birth. There was a trend towards greater age and more stage III cancer in the group with synchronous disease. There was no correlation between receiving radiotherapy for the first breast cancer and development of the second cancer. Annual mammography and clinical examination of asymptomatic women at a cancer centre resulted in the detection of a significantly higher proportion of minimal breast cancers in the second breast compared with the first. Such screening practices should be even more valuable in the earlier detection of unilateral breast cancer in asymptomatic women who have not had breast cancer.     

Progress and challenges in screening for early detection of ovarian cancer

Ovarian cancer is characterize by few early symptoms, presentation at an advanced stage, and poor survival. As a result, it is the most frequent cause of death from gynecological cancer. During the last decade, a research effort has been directed toward improving outcomes for ovarian cancer by screening for preclinical, early stage disease using both imaging techniques and serum markers. Numerous biomarkers have shown potential in samples from clinically diagnosed ovarian cancer patients, but few have been thoroughly assessed in preclinical disease and screening. The most thoroughly investigated biomarker in ovarian cancer screening is CA125. Prospective studies have demonstrated that both CA125 and transvaginal ultrasound can detect a significant proportion of preclinical ovarian cancers, and refinements in interpretation of results have improved sensitivity and reduced the false-positive rate of screening. There is preliminary evidence that screening can improve survival, but the impact of screening on mortality from ovarian cancer is still unclear. Prospective studies of screening are in progress in both the general population and high-risk population, including the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), a randomized trial involving 200,000 postmenopausal women designed to document the impact of screening on mortality. Recent advances in technology for the study of the serum proteome offer exciting opportunities for the identification of novel biomarkers or patterns of markers that will have greater sensitivity and lead time for preclinical disease than CA125. Considerable interest and controversy has been generated by initial results utilizing surface-enhanced laser desorption/ionization (SELDI) in ovarian cancer. There are challenging issues related to the design of studies to evaluate SELDI and other proteomic technology, as well as the reproducibility, sensitivity, and specificity of this new technology. Large serum banks such as that assembled in UKCTOCS, which contain preclinical samples from patients who later developed ovarian cancer and other disorders, provide a unique resource for carefully designed studies of proteomic technology. There is a sound basis for optimism that further developments in serum proteomic analysis will provide powerful methods for screening in ovarian cancer and many other diseases.     

Is mammography indicated for women with defective BRCA genes? Implications of recent scientific advances for the diagnosis, treatment, and prevention of hereditary breast cancer

About 5% of breast cancer patients have inherited their disease because of a mutation in genes encoding either the BRCA-1 or BRCA-2 proteins. Inheriting one of these mutations confers a 50% to 87% risk of breast cancer. Many physicians faced with such a patient would, at a minimum, suggest increased and earlier screening for breast cancer by routine mammography.[1] Normally, regular mammographic screening combined with appropriate and prompt treatment can reduce mortality from breast cancer by 30% in women aged 50-59 years and by about 14%-18% in women aged 40-49. There are no controlled clinical trials for screening young women who have multiple first-degree relatives developing breast cancer before age 45, or those known to carry BRCA-1 or BRCA-2 mutations. In fact, recent advances point out that BRCA-1 and BRCA-2 gene products are needed to repair radiation damage to DNA.[4,5] Based on this finding, I propose that women with defective BRCA genes are likely to have an inordinate sensitivity to radiation, and this raises a question about the advisability of routinely screening these women by frequent mammography.     

Screening for lung cancer.

The survival from bronchogenic carcinoma is highly dependent upon stage at the time of treatment. This is particularly true for squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, but holds true for small cell carcinoma as well. The problem presented to the medical profession has been to find a practical means of detecting lung cancer while it is still at an early stage. Three studies in progress have indicated that a larger proportion of the patients may be found to have early stage lung cancer when screened with a combination of chest X-rays and sputum cytology. However, the detection of these early stage cases has not yet been translated into an improvement in the overall mortality rate from lung cancer.     

Noninvasive molecular biomarkers for the detection of colorectal cancer

Colorectal cancer (CRC) is the third most common malignancy in the world. Because CRC develops slowly from removable precancerous lesions, detection of the disease at an early stage during regular health examinations can reduce both the incidence and mortality of the disease. Although sigmoidoscopy offers significant improvements in the detection rate of CRC, its diagnostic value is limited by its high costs and inconvenience. Therefore, there is a compelling need for the identification of noninvasive biomarkers that can enable earlier detection of CRC. Accordingly, many validation studies have been conducted to evaluate genetic, epigenetic or protein markers that can be detected in the stool or in serum. Currently, the fecal-occult blood test is the most widely used method of screening for CRC. However, advances in genomics and proteomics combined with developments in other relevant fields will lead to the discovery of novel non invasive biomarkers whose usefulness will be tested in larger validation studies. Here, noninvasive molecular biomarkers that are currently used in clinical settings and have the potential for use as CRC biomarkers are discussed.     

Le cancer de la prostate: Acquis et challenges pour l'an 2000

Principles of the diagnosis and treatment of prostate cancer at any stage are still improving. Early diagnosis is accessible throughout the use of the PSA test associated with digital rectal examination which lead to indicate transrectal biopsies. This allowed to treat patients at an earlier stage and significantly improved prognosis in the case of organ confined disease. Progress made in the radical prostatectomy technique have contributed to decrease the postoperative morbidity and is the treatment of reference in clinically localized disease. Radiation therapy still remains a valuable alternative, however, results are more difficult to evaluate. Hormonal treatment using androgen deprivation is indicated at the stage of metastasis. LHRH agonist associated with anti antiandrogens are as much efficacious as surgical castration. Unfortunately, the prognosis of advanced disease remains unpredictable. Objectives for the future will be to improve the diagnostic and staging of prostate cancer et to better define therapeutic indications; better understand the effects of androgen deprivation; and to propose new therapies for hormone refractory cancers.     

Two-stage models for the analysis of cancer screening data

Methods are proposed for the analysis of the natural history of disease from screening data when it cannot be assumed that untreated preclinical disease always progresses to clinical disease. The methodology is based on a two-stage model for preclinical disease in which stage 1 lesions may or may not progress to stage 2, but all stage 2 lesions progress to clinical disease. The focus is on joint estimation of the total preclinical duration and the sensitivity of the screening test. A partial likelihood is proposed for the analysis of prospectively collected screening data, and an analogous conditional likelihood is proposed for retrospective data. Some special cases for the joint sojourn distribution of the two stages are considered, including the independent model and limiting models where the duration of stage 2 is short relative to stage 1. The methods are applied to a case-control study of cervical cancer screening in Northeast Scotland.     

Modeling the Natural History and Detection of Lung Cancer Based on Smoking Behavior

In this study, we developed a method for modeling the progression and detection of lung cancer based on the smoking behavior at an individual level. The model allows obtaining the characteristics of lung cancer in a population at the time of diagnosis. Lung cancer data from Surveillance, Epidemiology and End Results (SEER) database collected between 2004 and 2008 were used to fit the lung cancer progression and detection model. The fitted model combined with a smoking based carcinogenesis model was used to predict the distribution of age, gender, tumor size, disease stage and smoking status at diagnosis and the results were validated against independent data from the SEER database collected from 1988 to 1999. The model accurately predicted the gender distribution and median age of LC patients of diagnosis, and reasonably predicted the joint tumor size and disease stage distribution.     

Longitudinal multistage model for lung cancer incidence, mortality, and CT detected indolent and aggressive cancers

It is currently not known whether most lung cancers detected by computerized tomography (CT) screening are aggressive and likely to be fatal if left untreated, or if a sizable fraction are indolent and unlikely to cause death during the natural lifetime of the individual. We developed a longitudinal biologically-based model of the relationship between individual smoking histories and the probability for lung cancer incidence, CT screen detection, lung cancer mortality, and other-cause mortality. The longitudinal model relates these different outcomes to an underlying lung cancer disease pathway and an effective other-cause mortality pathway, which are both influenced by the individual smoking history. The longitudinal analysis provides additional information over that available if these outcomes were analyzed separately, including testing if the number of CT detected and histologically-confirmed lung cancers is consistent with the expected number of lung cancers "in the pipeline". We assume indolent nodules undergo Gompertz growth and are detectable by CT, but do not grow large enough to contribute significantly to symptom-based lung cancer incidence or mortality. Likelihood-based model calibration was done jointly to data from 6878 heavy smokers without asbestos exposure in the control (placebo) arm of the Carotene and Retinol Efficacy Trial (CARET); and to 3,642 heavy smokers with comparable smoking histories in the Pittsburgh Lung Screening Study (PLuSS), a single-arm prospective trial of low-dose spiral CT screening for diagnosis of lung cancer. Model calibration was checked using data from two other single-arm prospective CT screening trials, the New York University Lung Cancer Biomarker Center (NYU) (n=1,021), and Moffitt Cancer Center (Moffitt) cohorts (n=677). In the PLuSS cohort, we estimate that at the end of year 2, after the baseline and first annual CT exam, that 33.0 (26.9, 36.9)% of diagnosed lung cancers among females and 7.0 (4.9,11.7)% among males were overdiagnosed due to being indolent cancers. At the end of the PLuSS study, with maximum follow-up of 5.8years, we estimate that due to early detection by CT and limited follow-up, an additional 2.2 (2.0,2.4)% of all diagnosed cancers among females and 7.1 (6.7,8.0)% among males would not have been diagnosed in the absence of CT screening. We also find a higher apparent cure rate for lung cancer among CARET females than males, consistent with the larger indolent fraction of CT detected and histologically confirmed lung cancers among PLuSS females. This suggests that there are significant gender differences in the aggressiveness of lung cancer. Females may have an inherently higher proportion of indolent lung cancers than males, or aggressive lung cancers may be brought into check by the immune system more frequently among females than males.     

Consequences of the widespread use of antibiotics

The cancer problem is increasing as life expectancy increases and greater portions of the populace live to the age at which cancer is more likely. Early diagnosis still is difficult. Even with modern methods and with considerable public education with regard to cancer, the disease is often not diagnosed until it is beyond the stage at which cure might be effected. The need for a serodiagnostic test for general screening purposes for cancer detection is tremendous. The major objective of cancer serodiagnostic test methods is to discover a general test that will detect cancer in a high percentage of cases while it is in an early stage; that will give few "false positive" results; that can be done in any laboratory; and that is simple and inexpensive. Many serodiagnostic tests for cancer have been published but none has proven worthy of being a good general test to detect cancer. Yet unless some serodiagnostic test which will be suitable for general screening purposes is developed, it is difficult to see how there can be much improvement in the early diagnosis of cancer, particularly internal cancer. It is hoped that an open-minded attitude will be maintained by physicians on this subject. Recent reports of such a test being developed are encouraging and it is hoped that continued investigations will be confirmatory.