The RECQL4 gene provides instructions for producing RecQ helicases, which are enzymes that bind to DNA and temporarily unwind its double helix, affecting cell replication, transcription, recombination, and damaged DNA repair. It plays a role in cells that develop bones and skin, and it is thought to be a tumor suppressor gene.

Because of its high expression in malignant cells, RECQ4 is considered a potential target for cancer therapy and is an active area of research.

Cancer Risk

Homozygous: Being identified as homozygous for pathogenic variants in RECQL4 is associated with several conditions. Rothmund-Thomson syndrome (RTS) is a rare disease characterized by a distinctive skin rash (poikiloderma), juvenile cataracts, sparse hair, and increased risk of developing osteosarcoma and non-melanoma skin cancers. Other associated conditions include RAPADILINO syndrome and Baller-Gerold syndrome. All three of these autosomal recessive conditions are associated with small stature.

Heterozygous: Malignancy risk in individuals who are heterozygous for pathogenic variants in RECQL4 is not entirely clear. Heterozygous germline RECQL4 pathogenic variants may be associated with an increased risk of a variety of malignancies, including bladder, colorectal, prostate, pancreatic, and male and female breast cancer (although the exact breast cancer risk is not clear), which makes it a potential susceptibility biomarker. The National Comprehensive Cancer Network (NCCN) considers it a low-penetrance gene, so heterozygotes’ likelihood of developing breast cancer may not be much higher than that of the general population.

RECQL4 is identified on many breast cancer germline testing panels, but presently we have no evidence-based recommendations for care. Research is ongoing to better understand the risks in individuals with a pathogenic RECQL4 variant.

Tumor Expression

Elevated RECQL4 protein expression is associated with poor prognosis in patients with gastric adenocarcinoma, making it a potential prognostic biomarker.

In patients with acute myeloid leukemia, low RECQL4 and BLM expression is linked to a poorer prognosis, whereas overexpression of RECQL4 indicates a better prognosis. In patients with multiple myeloma, overexpression of RECQL1, WRN, and RECQL4 is associated with poor prognosis. RECQL4 overexpression may also correlate with increased tumor aggressiveness in prostate cancer, and it may be a prognostic indicator for aggressive breast cancer.

Evidence also suggests that RECQL4 is a predictive biomarker, which may guide treatment decisions. High RECQL4 expression has been associated with increased resistance to cisplatin treatment in gastric cancer and breast cancer. Tumors with increased RECQL4 expression may also be resistant to radiation therapy.

Nursing Implications

Individuals with a pathogenic RECQL4 variant who may have increased risk for breast cancer should be managed based on family and personal history using standardized guidelines, such as those from NCCN. Some assigned female patients may benefit from more intensive screening. Male-assigned patients should be instructed on breast self-awareness. Screening recommendations for other cancers should follow NCCN or American Cancer Society guidelines. Patient education should include that our understanding about the risks associated with RECQL4 are evolving.

Families with germline risk should be referred to a genetics professional for questions about testing other family members when the meaning of the risk conferred is not completely clear. Heterozygotes of reproductive age should be offered the option of preconception testing because if their partner is also heterozygous, their offspring have a 25% chance of being homozygous and at risk for RTS, RAPADILINO, or Baller-Gerold syndrome.

Nurses can help patients understand the difference between germline and somatic testing and provide information about RECQL4’s prognostic and predictive implications. Detection of a pathogenic RECQL4 variant can be confusing because researchers are still trying to uncover its meaning. Families with a germline pathogenic variant should check with their genetics professional every 12–18 months to determine whether new evidence is available, recommendations for care are appropriate, their family history is current, or if additional testing is needed.