New cancer type with PIK3CA mutations

August 16, 2016
New cancer type with PIK3CA mutations
Localization of PIK3CA mutations (relative to functional domains of encoded protein p110α) in colorectal and endometrial cancer by MSI type. Credit: Drs. Stacey Cohen and Colin Pritchard

A newly defined type of colorectal and endometrial cancer involves at least two somatic mutations in the mismatch repair genes (MMR): MLH1, MSH2, MSH6, PMS2. This double somatic MMR cancer has no germline mutations in the MMR genes, unlike tumors due to hereditary Lynch syndrome. Double somatic MMR cases, along with Lynch syndrome and MLH1 gene hypermethylation cases, exhibit microsatellite instability (MSI). This hypermutable phenotype is caused by the loss of DNA mismatch repair activity.

There is a need to improve our understanding of the molecular features distinguishing these three MSI subgroups. Doing so can better inform future risk and can potentially lead to new therapies.

Drs. Stacey Cohen (Clinical Research Division), Colin Pritchard (Department of Lab Medicine), and colleagues sought out to accomplish this. The investigators compared the molecular features of double somatic MMR, Lynch syndrome, MLH1 hypermethylated, and microsatellite stable (MSS) colorectal and endometrial cancers. Specifically, they examined the mutation prevalence among these cancer subgroups, focusing on mutations in five key in the epidermal growth factor receptor (EGFR) and phosphoinositide-3-kinase (PI3K) pathway: KRAS, NRAS, BRAF, PIK3CA, and PTEN. The results from their study were recently published in Gastroenterology.

Using two prospective studies, Hereditary Nonpolyposis Colorectal Cancer Study and the Ohio Colorectal Cancer Prevention Initiative, the investigators identified double somatic MMR patients as those with colorectal and endometrial tumors who had two or greater somatic (but not germline) mutations in MMR genes. Using targeted next-generation sequencing, they found among colorectal cancer cases that that 14/21 (67%) of patients with double somatic tumors also had PIK3CA mutations, compared to 4/18 (22%) of tumors from patients with Lynch syndrome, 2/10 (20%) tumors with MLH1 hypermethylation, and 12/78 (15%) tumors with microsatellite stability (Fisher's exact test, P<.0001 for patients with double somatic tumors vs. other subgroups). Among endometrial cancer cases, mutations in PIK3CA were detected in all 13 patients with double somatic tumors (P=0.04 compared to other subgroups).

Using The Cancer Genome Atlas as an independent validation dataset (113 patients with colorectal tumors, 178 endometrial tumors), they found similar results: 100% of double somatic MMR cases carried a somatic mutation in PIK3CA (P<.0001 compared with other subgroups).

Dr. Pritchard comments on how these results could influence testing and possibly treatment of colorectal and endometrial cancer patients, "Many patients with colorectal and endometrial cancer have their tumors evaluated for MSI to screen for genetic predisposition to cancer caused by Lynch syndrome.  Our study suggests that mutations in PIK3CA are more frequently linked to a specific mechanism of microsatellite instability that is not related to Lynch syndrome.  The findings have implications for interpretation of MSI testing, and possibly for treatment selection, as PIK3CA mutations have been associated with responses to therapy." Dr. Cohen elaborates, "We are now recognizing that colorectal cancer is made up of many different types that can be categorized by genetics changes in the tumor. Lynch syndrome is well known for the associated increased predisposition to colorectal, endometrial, and other cancers. We described cancers that can mimic the changes in Lynch syndrome. This has important implications for trying to tailor treatment to an individual patient's cancer."

In terms of future direction, Dr. Pritchard notes, "From the standpoint of biology, it would be useful to study the underlying mechanism for the higher frequency of PIK3CA in double somatic colon and endometrial cancers.  From the standpoint of clinical care, we need to study how PIK3CA mutation status may be used to assist in MSI testing and Lynch syndrome workup."

Explore further: Evidence mounts for endometrial cancer tumor testing to identify women with Lynch syndrome

More information: Stacey A. Cohen et al. Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes, Gastroenterology (2016). DOI: 10.1053/j.gastro.2016.06.004

Related Stories

Evidence mounts for endometrial cancer tumor testing to identify women with Lynch syndrome

December 11, 2013
A recent article by Norris Cotton Cancer Center researchers published in the January 2014 issue of the journal Clinical Chemistry reviews the scientific evidence that warrants screening all endometrial cancers for Lynch syndrome. ...

Study identifies genetic mutations associated with cancer risk for hereditary cancer syndrome

June 5, 2011
(Medical Xpress) -- Among various genetic mutations for individuals with Lynch syndrome, a hereditary cancer syndrome that carries a high risk of colon cancer and an above-normal risk of other cancers, researchers have identified ...

AGA recommends all patients with colorectal cancer get tested for Lynch syndrome

September 10, 2015
All colorectal cancer patients should undergo tumor testing to see if they carry Lynch syndrome, the most common inherited cause of colorectal cancer, according to a new guideline published in Gastroenterology, the official ...

Association between genetic condition, hormonal factors, and risk of endometrial cancer

July 7, 2015
For women with Lynch syndrome, an association was found between the risk of endometrial cancer and the age of first menstrual cycle, having given birth, and hormonal contraceptive use, according to a study in the July 7 issue ...

Study shows potential new way to detect colorectal and other cancers

April 25, 2013
A unique new study led by University of Kentucky Markey Cancer Center researchers Guo-Min Li and Libya Gu, in collaboration with Dr. Wei Yang at National Institutes of Health, reveals a novel mechanism explaining the previously ...

Genetic cause of 15 percent of colorectal cancer diagnoses identified

July 19, 2016
Up to 15 percent of colorectal cancers show a genetic mutation known as DNA mismatch repair deficiency, or dMMR. Until now, little has been known about how the mutation behaves in rectal cancer patients, what causes dMMR, ...

Recommended for you

Study prompts new ideas on cancers' origins

December 16, 2017
Rapidly dividing, yet aberrant stem cells are a major source of cancer. But a new study suggests that mature cells also play a key role in initiating cancer—a finding that could upend the way scientists think about the ...

What does hair loss have to teach us about cancer metastasis?

December 15, 2017
Understanding how cancer cells are able to metastasize—migrate from the primary tumor to distant sites in the body—and developing therapies to inhibit this process are the focus of many laboratories around the country. ...

Cancer immunotherapy may work better in patients with specific genes

December 15, 2017
Cancer cells arise when DNA is mutated, and these cells should be recognized as "foreign" by the immune system. However, cancer cells have found ways to evade detection by the immune system.

Scientists pinpoint gene to blame for poorer survival rate in early-onset breast cancer patients

December 15, 2017
A new study led by scientists at the University of Southampton has found that inherited variation in a particular gene may be to blame for the lower survival rate of patients diagnosed with early-onset breast cancer.

Scientists unlock structure of mTOR, a key cancer cell signaling protein

December 14, 2017
Researchers in the Sloan Kettering Institute have solved the structure of an important signaling molecule in cancer cells. They used a new technology called cryo-EM to visualize the structure in three dimensions. The detailed ...

'Bet hedging' explains the efficacy of many combination cancer therapies

December 14, 2017
The efficacy of many FDA-approved cancer drug combinations is not due to synergistic interactions between drugs, but rather to a form of "bet hedging," according to a new study published by Harvard Medical School researchers ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.