AS508 – Prevalence and penetrance of breast cancer-associated mutations identified by multiple-gene sequencing

[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  [akurian@stanford.edu ]

Abstract

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:

Primary

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.

Secondary

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-­

carriers.

Exploratory

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.

 References

    breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum

    Genet. 2014.

    hereditary cancer risk assessment. J Clin Oncol. 2014;;32(19):2001-­2009.

   using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A.

   susceptibility: out on the high wire without a net? J Clin Oncol. 2013;31(10):1267-­1270.

   clinical exome and genome sequencing. Genet Med. 2013; 15(7):565-­574.