Chromosome 11p15: Its Role in Growth, Syndromes & Cancer

The human genome is organized into 23 pairs of chromosomes, which contain the genetic instructions for development and function. Chromosome 11 is one of these pairs and contains an estimated 1,300 to 1,400 genes. A specific segment of chromosome 11, known as 11p15, is located on its short arm. This area is a focal point for genetic research because it contains a dense cluster of genes that impact human growth and development. The proper functioning of this region is necessary for health, while alterations can lead to various medical conditions.

Genes and Imprinting on Chromosome 11p15

The 11p15 region contains genes that regulate growth, their activity controlled by a mechanism called genomic imprinting. This process turns genes on or off depending on which parent they were inherited from. For certain genes, only the copy from the mother is active, while for others, only the copy from the father is expressed. This parent-of-origin expression is established by chemical tags, known as methylation, on the DNA.

This region is organized into two imprinted domains, each governed by an imprinting control region (ICR): ICR1 and ICR2. The ICR1 domain manages the IGF2 gene, which produces a protein that promotes growth, and the H19 gene, which acts as a growth suppressor. The paternal copy of IGF2 is active, and the maternal copy of H19 is active.

The second domain, ICR2, controls another set of genes, including CDKN1C and KCNQ1OT1. The CDKN1C gene, expressed from the maternal chromosome, provides instructions for a protein that restricts cell growth. The KCNQ1OT1 gene, expressed from the paternal chromosome, helps regulate other genes in this domain. The coordinated action of these genes is important for balanced growth.

Beckwith-Wiedemann and Russell-Silver Syndromes

Disruptions in the regulation of genes on chromosome 11p15 can lead to two contrasting growth disorders: Beckwith-Wiedemann syndrome (BWS) and Russell-Silver syndrome (RSS). BWS is an overgrowth syndrome, with affected individuals often larger than normal at birth. Common features include an enlarged tongue (macroglossia), abdominal wall defects, and an increased risk of developing certain childhood cancers.

The genetic changes leading to BWS cause an increase in growth-promoting signals from the 11p15 region. This can happen through mechanisms such as errors in methylation at ICR1, leading to activation of both copies of the IGF2 gene. Another cause is paternal uniparental disomy (pUPD), where an individual inherits both copies of chromosome 11 from their father. Mutations that inactivate the maternally expressed CDKN1C growth suppressor gene can also cause BWS.

In contrast, Russell-Silver syndrome is characterized by restricted growth, both before and after birth. Children with RSS are small for their gestational age and have difficulty gaining weight. They may also have distinct facial features, such as a small, triangular face and a prominent forehead. The underlying molecular issues in RSS are often the opposite of those in BWS.

Many cases of RSS are caused by methylation defects at ICR1 on the maternal chromosome, which leads to decreased activity of the growth-promoting IGF2 gene. Another cause is maternal uniparental disomy, where an individual inherits both copies of chromosome 11 from their mother. This results in an imbalance of gene expression that favors growth restriction.

Chromosome 11p15 and Cancer Links

Alterations in the 11p15 region are linked to developmental syndromes and the formation of certain cancers, particularly pediatric tumors. The most prominent example is Wilms’ tumor, a type of kidney cancer that affects children. The connection involves the same genes that are disrupted in BWS, highlighting a shared pathway between abnormal growth and tumor formation.

One mechanism in Wilms’ tumor is a “loss of heterozygosity” at 11p15. This occurs when a cell loses the maternal copy of this chromosomal region and duplicates the paternal copy. This event leads to an overexpression of the growth-promoting IGF2 gene and a loss of the tumor-suppressing H19 and CDKN1C genes, creating an environment that encourages uncontrolled cell proliferation.

Beyond Wilms’ tumor, changes in the 11p15 region have been associated with other cancers, including rhabdomyosarcoma and adrenocortical carcinoma. In these contexts, the disruption of the balance between growth-promoting and growth-suppressing genes contributes to the disease. The increased cancer risk in individuals with BWS is linked to specific changes like pUPD or ICR1 methylation defects.

Diagnosis and Genetic Support

Identifying abnormalities in the chromosome 11p15 region requires specialized genetic testing. The diagnostic process begins with a physical evaluation by a clinician familiar with growth disorders. If a condition like BWS or RSS is suspected, laboratory tests are used to analyze the 11p15 region for characteristic genetic and epigenetic changes.

Common diagnostic techniques include methylation analysis, which examines the chemical tags on the DNA within the ICR1 and ICR2 domains. Another method is chromosomal microarray analysis, which can detect copy number variations, such as deletions or duplications. This can also identify uniparental disomy. Direct sequencing of genes like CDKN1C may be performed to find specific mutations.

Receiving a diagnosis related to chromosome 11p15 has significant implications for a family, making genetic counseling an important part of the process. Genetic counselors help families understand inheritance patterns, the chances of the condition recurring, and the potential health implications. They provide support, helping families navigate the medical system and connect with resources. This guidance allows families to make informed decisions regarding health management, such as cancer screening protocols for BWS.