Genomics in Clinical Practice, Part 2: Expect the Unexpected

Kate M. O'Rourke


July 27, 2016

Editor's Note:
This is the second in a three-part series on Medscape Oncology designed to update and familiarize practicing oncologists with the most important issues in multiplex and genomic testing.

What can you expect when you dig into an individual's DNA to look for genes associated with cancer? Expect the unexpected. This was one of the common threads that ran through many presentations at the recent annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

Several speakers, including Victoria Raymond, MS, CGC, an adjunct clinical assistant professor at University of Michigan Medical School in Ann Arbor, highlighted the same particularly tricky patient case in their presentations: a 30-year-old healthy woman who presented to an ob/gyn with a reported family history of breast cancer in multiple relatives. The physician ordered a multiplex gene panel test that included 25 genes (Table 1). After the visit, the patient called the office back to say that she was mistaken and has no family history of breast cancer. The panel had already been sent, and when it came back, the woman was positive for a truncating germline mutation in CDH1 (c. 1003C>T;p.R335X).

Table 1. 25-Gene Panel

STK11, TP53,
deletion/duplication analysis

With an estimated 75% penetrance rate, CDH1 mutations carriers are at high risk for hereditary diffuse gastric cancer syndrome, a condition that increases the risk for diffuse-type gastric cancer and lobular breast cancer.[1] The average age at diagnosis is 38 years.

Clinical guidelines make several recommendations for patients diagnosed with a germline CDH1 mutation.[2,3] Because diffuse gastric cancer is very difficult to screen for and the lifetime risk of developing gastric cancer for CDH1 mutation carriers is very high—70% for men and 56% for women—prophylactic total gastrectomy is recommended at an early age. At-risk individuals who are not ready to undergo this drastic operation or who have declined surgery should be screened every 6-12 months by upper endoscopy with multiple random biopsies beginning 5-10 years before the earliest cancer diagnosis in the family. Women have an increased risk for lobular breast cancer, with a cumulative lifetime risk of 39% to 52%, and thus breast cancer screening is recommended starting at age 35 years or 10 years before the youngest age of breast cancer within the family. Thus, a CDH1 mutation has potentially serious implications for a patient.

But what is the risk in this 30-year-old woman? When clinicians obtained an accurate family history for the woman, they learned that she has three healthy brothers, a living mother 61 years of age, a maternal aunt with lung cancer diagnosed at 42 years of age, a maternal aunt with ovarian cancer diagnosed at age 44 years, and a maternal aunt diagnosed with thyroid cancer at 27 years of age. A maternal grandfather was diagnosed with lung cancer at age 60 years. Cascade genetic testing revealed that all three of her brothers were negative for a CDH1 mutation, as was her mother.

"We presume that her father was the carrier. He was adopted, with no family history, and he died of a heart attack at age 58 years," said Ms Raymond. "Now we have a CDH1 pathogenic mutation in a young woman who is 30 years old; she has no family history of any CDH1-related cancer, and you have to think about how you are going to manage her risk. This scenario raises a real clinical question: Could this actually be one of the highly penetrant pathogenic mutations that was paternally inherited, and we don't know the paternal family history to help determine the risk?"

"It is more and more common that we are finding these highly penetrant genes in families and individuals where it just does not fit," said Ms Raymond. In some cases, the identification of a mutation may be unexpected, but makes sense when the family history is revisited.

Gregory Idos, MD, an assistant professor of clinical medicine in the Division of Gastroenterology and Hepatology at University of Southern California, Los Angeles, highlighted two patient cases that yielded unexpected findings. In one, a 45-year-old woman presented to a clinician with a family history of endometrial cancer—specifically, a mother and a sister with endometrial adenocarcinoma before 50 years of age. The genetics provider furnished a differential diagnosis of the mismatch genes for Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM), as well as PTEN. "Surprisingly, a mutation was found in BRCA2," said Dr Idos.

The second case was a 65-year-old woman who had already had two personal cases of breast cancer and also had a younger sister with breast cancer. She was given a differential diagnosis that included BRCA1/BRCA2, PALB2, CHEK2, ATM, NBN, BARD1, and RAD51C. The woman was discovered to have a mutation in PMS2, which has recently been identified as a cancer susceptibility gene. Detection of mutations in genes other than BRCA1 and BRCA2 highlights the genetic heterogeneity of hereditary breast and ovarian cancer.[4] Studies have shown that factors that predict BRCA1/BRCA2 mutations do not predict mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group.[5]

"Identification of unexpected mutations broadens our understanding of cancer risk and genotype/phenotype correlations," said Dr Idos.

With more routine genetic and genomic testing, said Ms Raymond, clinicians will be able to aggregate more clinical data to help elucidate the actual risk of moderate-penetrance genes and help us understand what we want to do with the "well-described genes," which are perhaps not as well described as we once thought. "As we are doing new panel testing, we are starting to identify families that have mutations in genes that we thought [carried] really high lifetime risks for cancer—but surprisingly, [the families] have pretty unremarkable family histories," said Ms Raymond. "What does that mean for our understanding about the penetrance of cancer in these known inherited conditions?"

When clinicians first started rolling out genetic testing, they were fairly selective in the families they tested, sticking mostly to those with strong family histories, said Claudine Isaacs, MD, a professor of medicine and oncology and codirector of the Fisher Center for Hereditary Cancer and Clinical Genomics Research at Georgetown University. Thus, it was not surprising that penetrance analyses revealed that the lifetime risk for cancers associated with those genes were very high. Dr Isaacs said that a study just published in the Journal of Clinical Oncology aimed to determine the carrier frequency rate in the general population.[6]

It's an ever-shifting genetic landscape.

In that study, led by Australian investigators, scientists evaluated panel testing from roughly 2000 individuals with a strong history of breast cancer who had previously tested negative for BRCA1/BRCA2 and 2000 controls (cancer-free women who were recruited from mammographic screening panels).[6] Looking at 18 genes frequently included in breast cancer panels (Table 2), they found a hint toward an excess risk for actionable mutations in the cases compared with controls (4.0% vs 1.7%), but it was not statistically significant. There was a statistically significant excess in PALB2 (26 vs 4 cases) and TP53 (5 cases vs 0).

In a nutshell, the frequency of mutations in most breast cancer panel genes among individuals selected for possible hereditary breast cancer is low and, in many cases, is similar than that observed among cancer-free population controls. Although multigene panels significantly aid in cancer risk management and expedite clinical translation of new genes, they equally have the potential to provide clinical misinformation at the individual level if the data are not interpreted cautiously.[6] It's an ever-shifting genetic landscape. For example, RAD50 was originally identified as a potential breast cancer gene in a Finnish population, but subsequent data, including the recent Australian study, do not support this.[6]

Table 2. 18-Gene Panel

RAD50, STK11, TP53,

"We have a lot to learn about the moderate-penetrance genes in terms of actual cancer risk," said Dr Isaacs.

We have a lot to learn about the moderate-penetrance genes in terms of actual cancer risk

She said there is a lot to be learned, period. "We are in a land that is ever-shifting," said Dr Isaacs. "The field keeps evolving at an incredibly rapid pace."

Ms Raymond has disclosed no relevant financial relationships. Dr Idos disclosed research funding from Myriad. Dr Isaacs disclosed honoraria from Genentech/Roche, Pfizer, Genentech, and Novartis.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.