Screening of prostate cancer patients for chromosomal aberrations may help focus future research and treatment
Prostate cancer is on the rise in India as life expectancies increase, and already constitutes one of the leading causes of cancer-related death in men worldwide. The disease is difficult to treat, in part because it encompasses a range of causal mechanisms which researchers still struggle to understand. Even now, the primary risk factors cited for prostate cancer are generic – limited to gender, a family history of the disease, race, and advanced age. A handful of specific chromosomal aberrations have been strongly implicated in prostate cancer in the past decade, however, which may help treatment move away from chemotherapy and towards precise therapeutic targets. Thus far, extensive studies of the frequency of these sub-types across populations have been limited to the United States, Japan and China. Recent work by Bushra Ateeq and colleagues at the Indian Institute of Technology (IIT), Kanpur and the University of Michigan sought to extend these studies to India, where knowing the probability of different prostate cancer sub-types in the country could have important implications for future treatment strategies.
The study, published this March in the journal TheProstate, characterized prostate tumour samples from patients admitted to medical establishments in New Delhi, Lucknow and Kanpur for the major molecular abnormalities that have been correlated so far with prostate cancer. Although molecular sub-types of prostate cancer show a genetic component, their associated molecular abnormalities arise in somatic tissue (for example, as a consequence of environmental insult) and are therefore not themselves passed on to future generations. “The genetic component or cause for the susceptibility for these chromosomal aberrations is still unknown,” says Ateeq, who is presently an Assistant Professor and Intermediate Fellow of the Wellcome Trust/ DBT India Alliance at IIT Kanpur. Due to this unknown genetic component, different racial groups show tendencies towards different chromosomal aberrations correlated with prostate cancer.
In Caucasian-American populations, for example, over half of the prostate cancer cases studied showed the fusion of androgen-regulated gene TMPRSS2with one of the ETSfamily of transcription factors, leading to androgen-driven over-expression of aberrant ETS proteins. This variant was only found in 28% of prostate cancer patients of African descent and in 10-20% of Japanese and Chinese populations studied. By contrast, the over-expression of the serine protease inhibitor Kazal-type 1, SPINK1, is approximately twice as likely to occur in African-American prostate cancer patients (~24%) than Caucasian (10-15%).
Ateeq and colleagues found that patterns of distribution of molecular sub-types of prostate cancer in North India resembled those found in Caucasian populations, for the 96 tumour samples studied. About ~49% of the tumour samples were positive for aberrant ERG proteins (a member of the ETS transcription factor family), as opposed to 27% found by an earlier smaller study out of New Delhi in 2013. Likewise, SPINK1 over-expression was detected in ~12% of the cases, which again corresponds with levels in Caucasian populations. RAF gene rearrangements were detected in ~5.5% of the cases, and PTEN loss in ~21% of the cases. PTEN deletion overlapped with 30% of the ERG-positive cases, and only in one case with SPINK1 over-expression, which again mirrors results in other populations.
“We believe that molecular screening of prostate cancer will have a huge impact on the choice of treatment options,” says Ateeq. Knowing how prostate cancer manifests in India will help us optimize screening methods and select treatment regimens to explore, she says. Each variant of prostate cancer poses its own therapeutic challenges, but some prostate cancer sub-types might also respond to drugs that we already have. “Patients positive for RAF genetic rearrangements, which are ~5.5% of the total cases in India may benefit by FDA–approved RAF inhibitors,” says Ateeq.
The group also plans to extend their study in the future to include geographic regions beyond North India. The distribution of prostate cancer sub-types will likely vary across India, according to Ateeq, given the country’s genetic diversity. Concurrently, Ateeq is also looking at the role of SPINK1 over-expression in prostate cancer, with the goal of identifying new therapeutic strategies for treating the disease.