Genomic landscapes of cancers may help improve treatment
Last Updated: Thursday, May 02, 2013, 12:30
  

Washington: Two studies from The Cancer Genome Atlas (TCGA) program have provided new insights into the molecular underpinnings of acute myeloid leukemia (AML) and endometrial cancer with the potential to improve treatment.

Researchers behind the studies have revealed details about the genomic landscapes of these cancers.

These studies represent the sixth and seventh in a series of genomes of at least 20 major cancers.

A comprehensive genomic analysis of nearly 400 endometrial tumors suggests that certain molecular characteristics - such as the frequency of mutations - could complement current pathology methods and help distinguish between principal types of endometrial tumors, as well as provide insights into potential treatment strategies.

In addition, the study, led by investigators in The Cancer Genome Atlas (TCGA) Research Network, revealed four novel tumor subtypes, while also identifying genomic similarities between endometrial and other types of cancers, including breast, ovarian, and colorectal cancers.

These findings represent the most comprehensive characterization of the molecular alterations in endometrial cancers available to date.

Distinguishing between different types of endometrial cancers is currently based on histology, an examination of a thin slice of tissue under a microscope. But categorizing endometrial cancer tissues is often difficult, and specialists frequently disagree on the classification of individual cases.

In this study, investigators showed that approximately 25 percent of tumors that pathologists classified as high-grade endometrioid showed frequent mutations in TP53, a tumor suppressor gene, as well as extensive copy number alterations, a term for when a cell has too many or too few copies of a genomic segment.

Both are key molecular characteristics associated with serous tumors, along with a small number of DNA methylation changes, which are additions of a basic chemical unit to pieces of DNA. Most endometrioid tumors, by contrast, have few copy number alterations or mutations in TP53, though there are frequent mutations in other well known cancer-associated genes, including PTEN, another tumor suppressor gene, and KRAS, a gene involved in regulating cell division.

These data suggest that some high grade endometrioid tumors have developed a strikingly similar pattern of alterations to serous tumors, and may benefit from a similar course of treatment.

Investigators also found genomic similarities between endometrial cancers and other tumor types. Previous TCGA research showed that a form of ovarian cancer (high-grade serous ovarian carcinoma) and a subtype of breast cancer (basal-like breast cancer) share many genomic features.

In this study, the scientists found that endometrial serous carcinoma also has some of these same genomic characteristics. The cancers share a high frequency of mutations in TP53 (between 84 and 96 percent) and a low frequency in PTEN, with only 1 to 2 percent mutated.

Surprisingly, the researchers also found many shared characteristics between endometrioid tumors and colorectal tumors. Both cancer types demonstrate a high frequency of microsatellite instability, where the repair mechanism for DNA is broken, and mutations in POLE, a gene responsible for producing a protein involved in DNA replication and repair. These genomic changes led to high mutation rates in both tumor types.

With a complete analysis of the study`s findings, investigators have identified four novel genomic-based subtypes of endometrial cancer, which may set the stage for new diagnostic and treatment approaches. Each of the four genomic subtypes clustered together and was named for one of its notable characteristics:

The POLE ultramutated group was named for its unusually high mutation rates and hotspot mutations (sequences highly susceptible to mutation) in the POLE gene.

The hypermutated microsatellite instability group exhibited a high mutation rate, as well as few copy number alterations, but did not carry mutations in the POLE gene.

The copy number low group showed the greatest microsatellite stability but a high frequency of mutations in CTNNB1, a gene critical for maintaining the linings of organs, such as the endometrium.

The copy number high subtype was composed of mostly serous tumors, but included some endometrioid samples. This subtype displayed copy number alterations and a mutation landscape that was characteristic of serous tumors.

The findings were published in the journal Nature.

ANI


First Published: Thursday, May 02, 2013, 12:30



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