January 28, 2011

Personalized diagnostics/prognostics: Ovarian Cancer example

By: Douglas S. McNair, MD, PhD

A reader emailed me to ask: In follow-up to your previous blog post, is there a comparable example for women's health?

To be exactly comparable, we'd be talking about genomics-based personalized tailoring of cancer screening-related diagnostic testing normal-ranges or decision-levels, where the diagnostic involves a customary biomarker molecule that is used to assess risk of cancer and guide further evaluation or intervention.

And the answer is "Yes, there are some women's health comparables." They include non-small cell lung cancer in women, breast cancer, endometrial cancer, and ovarian cancer. But in each instance, the data are as yet not so well-established or extensive as is the case for genomics-adjusted PSA and prostate cancer.

For example, the biomarker CA-125 has been used for many years as a screening test for ovarian cancer, and for other purposes related to monitoring recurrence and progression of ovarian cancer. CA-125 is coded by the MUC16 gene on Chr. 19. There are 50 polymorphisms in MUC16 that are measured in a direct-to-consumer (DTC) genomics test like 23andme.

• rs1695 (GSTP1; 313A>G) on Chr. 11
• rs3957357 (GSTA1, glutathione S-transferase alpha-1; -69C>T) on Chr. 6 [not in 23andme]
• rs2295190 (SYNE1; 9793G>T) on Chr. 6 [not in 23andme]
• rs7797466 (PMS2; 1121G>A) on Chr. 7
• rs2227311 (RB1; -473T>C) on Chr. 13 [also rs4151620 and rs2854344]
• rs1042838 (PGR; 1978G>T) on Chr. 11 [also rs608995]
• rs523349 (SRD5A2; C>G) on Chr. 2

These are not in the DTC genomics companies' "reports", but the results are there in the raw file download that you receive from the companies, and you can go and look up your genotypes [except for the ones in square-brackets].

Per the studies linked below, if you have "AG" or "GG" genotype at the GSTP1 rs1695 SNP (variants associated with reduced GSTP1 function) you have a lower risk of getting ovarian cancer.

Additionally, if you do get ovarian cancer, the "AG" or "GG" genotypes confer a lower risk of disease progression. And if the ovarian cancer progresses it tends to progress more slowly than average. As a result, there is a significant 23% advantage in terms of improved survival among carriers of GSTP1 "GG" or "AG" genotypes who do get ovarian cancer.

But, in a manner that's analogous to the situation in the previous blog post with men and PSA levels, the "G" allele of rs1695 associated with lower-than-population-average baseline CA-125 levels are significantly less frequent among women with a negative biopsy or peritoneal cytology than in women who test positive for ovarian cancer. That means that, for women with the "GG" or "AG" genotypes, their low-percentile CA-125 levels will tend to cause false reassurance, 'stand-down' decisions on laparoscopy (due to the still-“normal” CA-125 level), diminished cancer detection opportunities when undergoing CA-125-based screening, and consequent failure to detect ovarian cancer early.

Several of the articles below are freely available in public domain, so we are able to attach the pdf files of them below for your convenience. For the others, go ahead and click on the links and browse the abstracts to see whether you may like to read them in their entirety on a pay-per-view basis.

Thank you for the email question!

http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1695
http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=3957357

Beeghly A, et al. Glutathione S-transferase polymorphisms and ovarian cancer treatment and survival. Gynecol Oncol. 2006;100:330-7.

Bol G, et al. Methylation profiles of hereditary and sporadic ovarian cancer. Histopathology. 2010;57:363-70.

Chang H, et al. Assessment of plasma DNA levels, allelic imbalance, and CA-125 as diagnostic tests for cancer. J Natl Cancer Inst. 2002;94:1697-703.
(download .pdf)