Doherty Lab Research

Overview

The main focus of research in the Doherty Lab includes features of prevention, prognosis, and survivorship as they relate to the molecular and genetic epidemiology of ovarian and lung cancers. Major research areas combine elements of ovarian and lung cancer histotyping and epidemiology, molecular biomarkers, race/ethnic disparities, understanding genomic variation for prevention and treatment, risk stratification, and lifestyle influences.

Ovarian Cancer

Ovarian cancer is challenging to study for a number of reasons. It is a rare disease and therefore screening tests require nearly perfect sensitivity and specificity to be effective, and it is typically diagnosed at a late stage, with poor survival. Accumulating evidence has led to the understanding that ovarian cancer is not a single disease; rather, it is thought that the various ovarian cancer histologic types and high grade serous (HGSC) molecular subtypes may have different etiologies. Furthermore, almost all research of the molecular epidemiology of ovarian cancer to date has been in women of European ancestry. Therefore, Dr. Doherty’s ovarian cancer research program has three main objectives:

1. To elucidate similarities and differences in epidemiologic and genetic risk factors and survival across the histologies and HGSC subtypes of ovarian cancer, with the goal of understanding the underlying causes of each so that preventive measures can be developed
2. To identify candidate genes and pathways that drive the development of each of the subtypes so that targeted treatments can be developed
3. To characterize epidemiologic and molecular features of ovarian cancer in diverse populations

In work supported by the V Foundation, we are seeking to understand racial and ethnic disparities in ovarian cancer treatment, recurrence, and mortality. This research was motivated by the fact that ovarian cancer is a leading cause of cancer death among US women, with about 50% of women dying from their disease within five years. Treatments including surgery and chemotherapy are meant to cure the cancer, but in about 50% of women, the cancer will come back.

Black and Hispanic women are more likely to stop treatment early, and to die from their disease than non-Hispanic white women. These differences are referred to as racial and ethnic disparities. There are many reasons for disparities, including differences in access and quality of medical care. Black and Hispanic women are also more likely to have other health conditions (i.e. comorbidities), like heart disease or diabetes, when they are diagnosed with ovarian cancer. These comorbidities may change a patient’s ability to tolerate treatment, and in turn, may reduce their survival. Comorbidities may also change the biology of the tumor. Examining tumor immune markers may provide information on response to treatment and survival of the patients.

In this V Foundation Thrivership award, we have leveraged data from the Kaiser Permanente Northern California Healthcare system to examine the influence of comorbidities in racial and ethnic disparities in ovarian cancer treatment, recurrence, and mortality. We have shown that Black patients are more likely to present with diabetes, hypertension, cardiovascular disease, and a higher net comorbidity burden at the time of their ovarian cancer diagnosis than other patients. We have also demonstrated that among all ovarian cancer patients, those who had comorbidities present at diagnosis had worse survival than those who did not.

Lung Cancer

Lung cancer is responsible for more deaths than prostate, breast, and colon cancers combined. While smoking cessation is a key means to reduce the incidence of lung cancer, former smokers remain at high risk for many years after quitting. Low-dose CT scan screening of high-risk individuals holds promise to reduce lung cancer mortality, but the false positive rate even among this high-risk group remains quite high.

Much of Dr. Doherty’s lung cancer work focuses on identifying factors of individuals with a heavy smoking history that differentiate between who will and who will not eventually develop lung cancer, with these goals: incorporating these factors into models for risk stratification for lung cancer screening regimens, and reducing false positive screens. Two potential biomarkers of lung cancer risk in heavy smokers studied by the Doherty Lab include telomere length and genome-wide DNA methylation, both assayed from blood taken prior to lung cancer diagnosis. These pre-diagnosis molecular features have also been assessed or are being assessed for their role in predicting survival.

Nevertheless, not all lung cancers can be attributable to smoking. Utah has the lowest rate of smoking in the country, yet approximately 20% of the lung cancer diagnoses in Utah occur in never-smokers. Given that never-smoking lung cancer cases are a historically understudied group in terms of risk, response to treatment, and survival, the Doherty Lab is interested in elucidating these features as well.