Checkpoint Kinase 2 Mutation

Introduction

Every cell in our body contains genes. Each gene from each parent is present in two copies in every cell. When genes function correctly, they aid in the prevention of cancerous cells. However, if one gene has a mutation, it cannot function.

What Is Checkpoint Kinase 2 (CHEK2)?

In reaction to DNA (deoxyribonucleic acid) damage, this serine/threonine kinase becomes active and involved in pathways that govern DNA repair, cell cycle arrest, or apoptosis (programmed cell death). In addition, it activates ATM (ataxia telangiectasia-mutated) phosphorylation of Thr68 (Threonine-68), which causes the gene to dimerize, allowing it to acquire kinase activity. Various types of cancer, most notably breast cancer, are linked to loss of kinase function.

What Is CHEK2 Gene Mutation?

• Most frequently associated with breast and colorectal cancer, CHEK2 mutations are found in gastric, prostate, ovarian, thyroid, lung, melanoma (a severe form of skin cancer), and glioblastoma (an aggressive form of brain cancer) cancers.

• CHEK2 gene mutation increases the risk of breast, colorectal, and prostate cancer.

• The majority of CHEK2 transformations are based on a mutation known as 1100delC- a cancer causing allele (one of different gene variants that can occupy a particular location).

• Approximately 1 % of Northern and Eastern European origin have this mutation.

• CHEK2 regulates cell division by preventing cell cycle arrest. As a result, CHEK2 is necessary for cell cycle regulation, and its abnormal expression may result in cancer.

• Several CHEK2 gene mutations have been identified, including

  1. 1100delC

  2. I157T

  3. R117G

  4. I160M

  5. G167R

  6. G167A.

• Among them, 1100delC and I157T are the most well-studied and have links to cancer susceptibility.

What Are the Cancers Associated With CHEK2 Mutations?

A. Breast Cancer- The average woman's lifetime chance of getting breast cancer is 10 %. For women with a CHEK2 mutation and a family history of breast cancer, the risk increases to 20–30 %. Women with a CHEK2 mutation who have previously had breast cancer are more likely to develop second, new breast cancer. Male breast cancer is sporadic, affecting less than 1 % of men in their lifetime. However, men with CHEK2 mutations have a slightly increased lifetime risk of developing breast cancer.

B. Colon Cancer- Colorectal cancer may be more common in people who have CHEK2 mutations. In addition, if colorectal cancer runs in the family, this risk rises.

C. Prostate Cancer- Men with CHEK2 mutations may have a slightly increased risk of prostate cancer.

What Are the Recommendations for Cancers Associated With CHEK2 Mutations?

1. Recommendations for Breast Cancer-

a. Women-

• Beginning at the age of 40, yearly mammogram and a breast MRI (magnetic resonance imaging) (scheduled six months apart).

• Women may consider taking Tamoxifen or Raloxifene to reduce their risk of breast cancer.

b. Men-

• Current prostate and breast cancer screening recommendations for men with CHEK2 mutations are the same as for the general population.

2. Recommendations for Colon Cancer-

a. Women and Men-

• Colonoscopy starts at age 40, every five years.

• People under 50 who have parents or siblings with colorectal cancer should begin screening ten years before their age at diagnosis.

• Cancer screening guidelines for people with CHEK2 mutations are updated regularly.

• Every few years, check in with the doctor or genetic counselor for updates on cancer risks and screenings.

b. Kids-

• Children of CHEK2 mutation carriers have a 50 % chance of inheriting the mutation. Therefore, after they reach the age of 18, they should undergo genetic testing and counseling.

c. Family Members Who Test Negative-

People who do not have the familial CHEK2 mutation are at the same risk as the general population for breast, prostate, and colorectal cancers. Family members who test negative for the CHEK2 mutation should consult their doctor or a genetic counselor to determine the best cancer screenings.

What Are the Risks Associated With the CHEK2 1100DELC Gene?

The Li-Fraumeni and Cowden syndromes were first associated with the CHEK2 1100delC allele. However, this mutation cannot be linked to these disorders because neither the mutation carriers nor their family members have these syndromes. Breast cancer risk increases in those who carry the CHEK2 1100delC allele, although it reduces in older people. Furthermore, carriers are more likely to develop estrogen receptor-positive breast cancer. However, there is no evidence that this risk is influenced by progesterone receptor (PR) or human epidermal growth factor receptor status.

What Are the Risks Associated With CHEK2 and Breast Cancer?

CHEK2 mutation carriers have a greater risk of breast cancer. When the carriers have first- and second-degree relatives afflicted, their risk is higher and connects with their family history. The risk is roughly 20 % in carriers with no affected relatives, and it can reach up to 44 % when both first- and second-degree relatives are affected. Only the 1100delC allele was discovered to influence breast cancer susceptibility in a study involving 2000 samples. Both men and women with the same mutation have an elevated chance of developing breast cancer, but the risk is unaffected by whether they also carry the BRCA1(breast cancer 1) or BRCA2 (breast cancer 2) mutation.

What Is the Role of the CHEK2 Gene in Chemotherapy?

Resistance to Anthracycline-based chemotherapy is linked to CHEK2 or TP53 (tumor protein 53) gene mutations in breast cancer patients. Women with breast cancer demonstrated that H371Y carriers might respond better to neoadjuvant chemotherapy. In contrast, there was no difference in response to adjuvant chemotherapy or endocrine therapy. Furthermore, CHEK2 variants have been linked to epirubicin response because allele carriers respond differently to this chemotherapeutic drug.

What Are the Uses of CHEK2 Mutations?

Therapies Using Biomarkers - CHEK2 mutation is a biomarker that predicts a patient's response to Olaparib (chemotherapy drug). The treatments using the CHEK2 mutation as a predictive biomarker have FDA (Food and Drug Administration) approval. Most treatments for CHEK2 mutation or its linked pathways are used in prostate cancer.

Conclusion

When DNA is damaged, the CHEK2 gene is activated. Additionally, it turns on particular genes that are essential for cellular processes like apoptosis, repair, and cell cycle arrest. In response to DNA damage, this serine/threonine kinase is activated, and it takes part in pathways that regulate DNA repair and other related pathways. Loss of kinase function has been associated with several cancer forms, most notably breast cancer. Although various mutations have been linked to an increased risk of breast cancer and a poor response to chemotherapy, the allele's low frequency complicates matters. Experimental data have been encouraging; however, studies evaluating the function of CHEK2 in conjunction with other genes may be more helpful in providing more accurate and reliable data.