[This page is intended to provide a study summary, the sections of which are below. Please complete these sections, as applicable. The headings below are suggested headings. You can remove inapplicable sections, or add new ones relevant to your study]
Investigator Names and Contact Information
Allison W. Kurian, M.D, M.Sc [firstname.lastname@example.org ]
Background: Breast cancer is a common disease, with most cases occurring in the absence of any known
cause. Recently, we and others identified mutations in 'moderate-penetrance' genes among a significant
proportion of women who tested negative for BRCA1 and BRCA2 (BRCA1/2) mutations, but the magnitude
of associated breast cancer risk is uncertain. Therefore, physicians lack sufficient evidence to counsel mutation carriers
about risk-appropriate strategies for cancer screening and prevention.1-4 The Women's Health Initiative (WHI) offers
breast cancer cases diagnosed in post-menopausal women who were unselected for age of onset, family cancer history or
other high-risk features along with appropriate controls, enabling a highly informative study of mutation prevalence and
penetrance that will generalize to the U.S. population.
Aims: The specific aims are to determine 1) the prevalence and penetrance (breast cancer risk) of inherited
mutations of four specific genes identified by next-gene sequencing (NGS) in WHI participants who developed
invasive breast cancer and controls who did not ; 2) the prevalence and penetrance of other genes identified by
next-gene sequencing; and 3) the survival of breast cancer patients with and without these inherited gene mutations.
Methods: We will use massively parallel NGS to analyze 28 genes using DNA samples of 2,500 WHI
participants who developed breast cancer and 2,500 controls. Genes were selected according to published
literature, and will include those in sequencing panels that are increasingly used in clinical practice.5
Deleterious mutations and variants of uncertain clinical significance will be defined according to guidelines of
the American College of Medical Genetics (ACMG).6 We will use a nested case-control study design to
determine i) the prevalence of inherited mutations in specific genes among women who did and did not
develop breast cancer; and ii) the penetrance, or magnitude of breast cancer risk, associated with mutations in
specific genes. We will compare survival outcomes between breast cancer patients with and without inherited
mutations in specific genes.
Significance: This study will determine the prevalence and magnitude of breast cancer risk associated with
inherited mutations in many cancer-associated genes, which are increasingly detected by routine genetic tests
but whose clinical implications are very poorly understood. The knowledge to be gained will guide risk-adapted
strategies for breast cancer prevention, and has tremendous potential to reduce morbidity and mortality.
Hypothesis and Specific Aims
The hypothesis is that fully sequencing a panel of 28 cancer-associated genes will identify potentially causal
mutations for invasive breast cancer, in addition to the known effects of mutations in BRCA1/2. A further
hypothesis is that survival varies with inherited mutations in specific genes. We will test these hypotheses with
the following specific aims:
Specific Aim 1: Determine the prevalence and penetrance of inherited mutations of four specific genes in
WHI participants who developed invasive breast cancer and controls who did not.
These four genes were selected for the primary aim because their prevalence and penetrance
are less well understood than BRCA1 and BRCA2, yet prior research has identified them as being
important genes in hereditary breast cancer.
Specific Aim 2: Determine the prevalence and penetrance of inherited mutations of BRCA1 and BRCA2
genes in breast cancer cases compared to the controls.
Specific Aim 3: Determine the prevalence and penetrance of inherited mutations of seven other genes which may
be associated with breast cancer in breast cancer cases compared to the controls.
Specific Aim 4: Determine the prevalence and penetrance of inherited mutations of five genes associated with
Lynch Syndrome in breast cancer cases compared to the controls.
Specific Aim 5: Determine the breast cancer-specific and overall survival among the breast cancer patients
with and without the inherited mutations of the four selected genes (mentioned in specific aim 1).
In addition, identify the patient, tumor, and treatment factors associated with survival among mutation carriers and non-
Specific Aim 6: Determine the prevalence and penetrance of inherited mutations of other genes which are
part of the 25-gene panel in breast cancer cases compared to controls.
Specific Aim 7: Determine the breast cancer-specific and overall survival among the breast cancer patients
with and without other inherited mutations (excluding those in Specific Aim 5). In addition, identify the
patient, tumor, and treatment factors associated with survival among mutation carriers and non-carriers.
1. Castera L, Krieger S, Rousselin A, et al. Next-generation sequencing for the diagnosis of hereditary
breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum
2. Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for
hereditary cancer risk assessment. J Clin Oncol. 2014;;32(19):2001-2009.
3. Tung NB, C.; Allen, B.; Kaldate, R.; Soltis, K.; Timms, K.; Bhatnagar, S.; Bowles, K.; Roa, B.; Wenstrup,
R.; Hartman, A.-R. Prevalence of gene mutations among hereditary breast and ovarian cancer patients
using a 25 gene panel. San Antonio Breast Cancer Symposium;; December, 2013;; San Antonio, Texas.
4. Walsh T, Lee MK, Casadei S, et al. Detection of inherited mutations for breast and ovarian cancer
using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A.
5. Domchek SM, Bradbury A, Garber JE, Offit K, Robson ME. Multiplex genetic testing for cancer
susceptibility: out on the high wire without a net? J Clin Oncol. 2013;31(10):1267-1270.
6. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in
clinical exome and genome sequencing. Genet Med. 2013; 15(7):565-574.