CRC-Associated Gene Alteration May Raise Likelihood of Other Solid Tumors

"Can we target the BER pathway for possible drug sensitivities? If so, doctors might be able to add a new therapeutic approach to their arsenal of tools against solid cancers," according to Channing Paller, MD.

A pan-tumor assessment of MUTYH alterations in solid tumor malignancies highlighted that biallelic MUTYH inactivation plus somatic loss of heterozygosity (LOH) is expressed in several malignancies outside of colorectal cancer (CRC), according to findings published in JCO Precision Oncology.¹

Of available tissue biopsies from 354,366 patients, 1.9% (n = 6572) harbored MUTYH alterations, which included 119 samples that had a biallelic inheritance. Of 5982 samples with monoallelic MUTYH mutations, 88% (n = 5244) were predicted to be heterozygous and lost wild-type MUTYH alleles were predicted in 12% (n = 738). Additionally, samples with MUTYH LOH tended to have higher rates of Chr 1p loss, highlighting it as a common pathway in which MUTYH is inactivated. Investigators noted that MUTYH LOH may be observed when an entire chromosome is lost or homologous recombination repair deficiency without chromosome loss occurs.

Most tumor samples with biallelic germline pathogenic variants of MUTYH were CRCs (66%; n = 78/119), although investigators observed some cases of small intestine and other cancers. Additionally, 14% (n = 104/738) of samples with a monoallelic pathogenic variant and LOH were CRCs.

Cancer types that had excessive germline MUTYH heterozygous alterations consisted of pancreas islet cell tumors (3.3%), adrenal gland cancer (3.0%), germ cell tumors (3.0%), thyroid medullary cancer (2.4%), thymus cancer (2.3%), and bone sarcomas (2.2%). Monoallelic MUTYH variants were less prominent in hormonally-driven cancers including breast cancer, prostate cancer, uterine cancer, endometrial cancer, and ovarian cancer, with rates ranging from 1.3% to 1.7% across these types.

“We know 2 missing copies of MUTYH greatly increases the risk of colon cancer, and now it appears that having only 1 missing copy may lead to a small increased risk of other cancer types,” lead study author Channing Paller, MD, the director of prostate cancer clinical research and an associate professor of Oncology at the John Hopkins University School of Medicine, said in a press release on these findings.² “The next question is whether this finding has therapeutic implications. Can we target the BER pathway for possible drug sensitivities? If so, doctors might be able to add a new therapeutic approach to their arsenal of tools against solid cancers.”

Investigators assessed tumor samples from patients who received routine clinical care between August 2014 and February 2022. Comprehensive genomic profiling (CGP) consisted of formalin-fixed paraffin-embedded tissue biopsy sections using FoundationOne or FoundationOne CDx, with histologic diagnoses being confirmed with routine hematoxylin and eosin–stained slides.

Investigators computationally inferred the germline or somatic origin of a specific MUTYH variant with a validated somatic/germline zygosity (SGZ) algorithm, which is designed to leverage read depth and the local variability of single-nucleotide polymorphism allele frequencies. Additionally, the algorithm was used to classify the zygosity of a variant in a tumor as heterozygous, homozygous, or uncertain.

Across the overall cohort, p.G396D (rs36053993) and p.Y179C (rs34612342) were the 2 most common pathogenic MUTYH variants. Their distributions were comparable in sample groups that had a biallelic inheritance, heterozygous status, and LOH.

Over 2% of adrenal gland cancers and pancreatic islet cell tumors were found to have germline MUTYH variants in combination with somatic LOH. Cancer types with more prevalent LOH, which included those with more frequent loss of chromosome 1p, generally consisted of pancreas islet cell tumors, adrenal gland tumors, bone sarcomas, and gastrointestinal stromal tumors. Melanoma, bladder cancer, and other cancer types with typically high mutational burden were reported to have low SBS18 scores.

References

1. Pan-cancer interrogation of MUTYH variants reveals biallelic inactivation and defective base excision repair across a spectrum of solid tumors. JCO Precis Oncol. Published online February 23, 2024. doi:10.1200/PO.23.00251
2. Colorectal cancer gene implicated in broad range of solid tumors. News release. John Hopkins Medicine. March 25, 2024. Accessed April 1, 2024. https://tinyurl.com/4fjnev9t