Pan-Cancer Interrogation of MUTYH Variants Reveals Biallelic Inactivation and Defective Base Excision Repair Across a Spectrum of Solid Tumors
Abstract
Purpose
Biallelic germline pathogenic variants of the base excision repair (BER) pathway gene MUTYH predispose to colorectal cancer (CRC) and other cancers. The possible association of heterozygous variants with broader cancer susceptibility remains uncertain. This study investigated the prevalence and consequences of pathogenic MUTYH variants and MUTYH loss of heterozygosity (LOH) in a large pan-cancer analysis.
Materials and Methods
Data from 354,366 solid tumor biopsies that were sequenced as part of routine clinical care were analyzed using a validated algorithm to distinguish germline from somatic MUTYH variants.
Results
Biallelic germline pathogenic MUTYH variants were identified in 119 tissue biopsies. Most were CRCs and showed increased tumor mutational burden (TMB) and a mutational signature consistent with defective BER (COSMIC Signature SBS18). Germline heterozygous pathogenic variants were identified in 5,991 biopsies and their prevalence was modestly elevated in some cancer types. About 12% of these cancers (738 samples: including adrenal gland cancers, pancreatic islet cell tumors, nonglioma CNS tumors, GI stromal tumors, and thyroid cancers) showed somatic LOH for MUTYH, higher rates of chromosome 1p loss (where MUTYH is located), elevated genomic LOH, and higher COSMIC SBS18 signature scores, consistent with BER deficiency.
Conclusion
This analysis of MUTYH alterations in a large set of solid cancers suggests that in addition to the established role of biallelic pathogenic MUTYH variants in cancer predisposition, a broader range of cancers may possibly arise in MUTYH heterozygotes via a mechanism involving somatic LOH at the MUTYH locus and defective BER. However, the effect is modest and requires confirmation in additional studies before being clinically actionable.
Introduction
Cells are constantly exposed to both endogenous and exogenous oxidative stress—the former from byproducts of cellular respiration, the latter from exposures to various xenobiotics. MUTYH is a critical component of the base excision repair (BER) pathway and mediates repair of oxidative DNA damage from both endogenous and exogenous sources. Oxidative damage to DNA can lead directly to mutagenesis or programmed cell death.1,2 Because of this, cells have multiple mechanisms to detect and repair oxidative DNA damage.
Context
Key Objective
Although biallelic germline MUTYH mutations predispose carriers to colorectal cancers, the relationship between heterozygous variants and cancer predisposition remains unclear. This study investigated the prevalence and consequences of germline pathogenic MUTYH variants and MUTYH loss of heterozygosity (LOH) in a large pan-cancer analysis.
Knowledge Generated
Within this population, just under two percent of patients had a MUTYH mutation, with the majority being heterozygous. Twelve percent of the heterozygous patients showed MUTYH LOH, higher rates of chromosome 1p loss, and higher COSMIC SBS18 signature scores reflective of base excision repair (BER) deficiency. These cancers also have a modestly elevated tumor mutational burden (TMB).
Relevance
Therefore, in addition to the established role of biallelic pathogenic MUTYH variants in bowel cancer predisposition, a broader range of cancers may possibly arise in MUTYH heterozygotes via a mechanism involving somatic LOH at the MUTYH locus and defective BER. This opens the way for future studies to explore novel therapeutic strategies for BER-deficient cancers.
The most common product of oxidative damage to DNA is 8-oxo-7, 8-hydroxyguanine (8-oxoG).3 The average level of 8-oxoG is estimated to be 1-2 per 106 guanine residues in nuclear DNA and is approximately an order of magnitude higher in mitochondrial DNA owing to higher exposure to the reactive oxygen species formed during cellular respiration.4 8-oxoG can pair with both adenine and cytosine during DNA replication leading to G:C to T:A transversion mutations. MUTYH, by excising mismatched adenine, prevents these mutations and is a key part of the BER pathway. MUTYH is widely expressed and particularly active in tissue with both high exposure to oxidative damage and frequent cell divisions.5
Defects in the BER pathway are associated with both increased mutational burden and carcinogenicity.6 Individuals with homozygous or compound heterozygous (biallelic) germline MUTYH mutations develop MUTYH-associated polyposis (MAP), an autosomal recessive condition that typically manifests with adenomatous colorectal polyps and a greatly increased risk of colorectal cancer (CRC). Individuals with this syndrome are estimated to have an excess risk factor of 93-fold7,8 and the syndrome is a significant contribution to the incidence of CRC in individuals younger than 55 years. In the absence of surveillance and treatment, with age, penetrance may reach nearly 100%.9
Both colon polyps and normal intestinal tissue from individuals with MAP show a higher mutation burden than age-matched controls as well as a distinct tumor mutational signature, COSMIC signature SBS18,10 which is dominated by G:C -> T:A transversions. Nonetheless, among individuals with MAP, there is variation both in terms of total mutation burden as well as the overall contribution of the SBS18 signature.11
Whether monoallelic germline MUTYH carriers have an increased risk for cancer has been the subject of much controversy. Although some studies have found that heterozygous MUTYH mutations may predispose to CRC later in life, other studies have not,12 and the most recent analysis has indicated there was benefit for early surveillance for colon cancer in MUTYH heterozygotes in the presence of family history13 while a large-scale meta-analysis found that MUTYH variants were among the genes that conferred significant risk.14 A large case-control study focusing on a European population found no association between monoallelic MUTYH carrier status and risk for colon, breast, or endometrial cancer,15 while other studies have found an overall increase for several cancers.16
One possible carcinogenetic mechanism in heterozygous MUTYH carriers is somatic loss of the wild-type (WT) MUTYH allele, which may manifest as loss of heterozygosity (LOH).17 In individuals with germline mutations in tumor suppressor genes such as RB1 in retinoblastoma or BRCA1/2 in breast/ovarian and prostate cancer, LOH at the MUTYH locus represents the second hit in accordance with Knudson's two-hit hypothesis.18,19 Across all cancers, it is estimated that 16% of gene loci undergo LOH, but genomewide LOH rates are tumor-dependent and typically reflect rates of homologous recombination deficiency, with the highest average rates seen in adenoid cystic carcinoma (45%) and the lowest (0.1%) in thyroid carcinoma.20
A previous study using a small data set showed that although most cancers from heterozygous (monoallelic) MUTYH carriers showed no increase in tumor mutational burden (TMB), those with LOH at the MUTYH locus showed both higher TMB and association with the COSMIC SBS18 signature.6 A larger study, using allele frequency (AF) in sequenced tumors to infer germline mutation status, found a higher-than-expected prevalence of monoallelic germline MUTYH mutations in patients with cancer but confirmed that monoallelic mutation on its own was not associated with increased TMB or the COSMIC SBS18 signature, while cancers that also had somatic LOH at the MUTYH locus were associated with both features.21 Crucially, cancers from heterozygous MUTYH carriers that had LOH showed distinctive patterns of mutations in oncogenes such as KRAS and PIK3CA, suggesting that MUTYH inactivation, while not necessarily a driver, has the potential to accelerate tumor development, and is not a mere passenger during carcinogenesis.21
Here, we use the somatic/germline zygosity (SGZ) algorithm to infer germline and somatic MUTYH status in a very large data set from 354,366 tumor samples that had undergone comprehensive genomic profiling (CGP) using an next-generation sequencing-based hybrid capture–based assay. We confirm the association of inherited biallelic pathogenic MUTYH variants with CRC and, much less frequently, other cancers. We also observed the occurrence of acquired LOH at the MUTYH locus across a range of cancer types in association with a monoallelic inherited pathogenic MUTYH variant. These cancers showed slightly increased TMB and the COSMIC SBS18 signature, consistent with a late-stage two-hit mechanism underlying the development of some cancers in MUTYH heterozygotes.
Materials and Methods
Data
The study cohort consisted of tissue biopsies from 354,366 patients with solid tumors submitted for CGP during routine clinical care between August 2014 and February 2022. Approval for this study, including a waiver of informed consent and Health Insurance Portability and Accountability Act compliance, was obtained from the Western Institutional Review Board (protocol 20152817).
CGP
CGP was performed on formalin-fixed paraffin-embedded tissue biopsy sections using FoundationOne or FoundationOne CDx (median coverage: >860×), both of which cover the full coding sequence of MUTYH. The histologic diagnosis of each case was confirmed on routine hematoxylin and eosin–stained slides, and all samples contained a minimum of 20% tumor nuclei. The CGP platform is a validated hybrid capture–based assay performed in a Clinical Laboratory Improvement Amendment–certified, College of American Pathologists–accredited, New York State–approved commercial laboratory (Foundation Medicine, Cambridge, MA).22,23 F1 and F1CDx interrogate a total of 311 and 324 cancer-related genes, respectively, for base substitutions, short insertions and deletions, copy-number amplifications and homozygous deletions, and large genomic rearrangements, as well as microsatellite instability, TMB, and genomic LOH.
SGZ Algorithm
The germline or somatic origin of a particular MUTYH variant was computationally inferred using a previously described and validated algorithm (called SGZ) that leverages read depth and the local variability of single-nucleotide polymorphism allele frequencies.24 This algorithm also predicts the zygosity of a variant in the tumor: heterozygous, homozygous, or uncertain. SGZ classifies a variant as inferred to be somatic or germline on the basis of its AF, considering the tumor content (proportion of neoplastic nuclei), tumor ploidy, and the local copy number. At the sequencing depths in this study, the SGZ algorithm is expected to have an accuracy of approximately 85% in predicting germline or somatic status.24 Samples with at least one germline pathogenic MUTYH mutation were classified as germline biallelic (if a second germline alteration was found), germline with somatic (if a somatic alteration was found—no sample contained more than two variants), germline monoallelic with LOH at the MUTYH locus, or germline monoallelic without LOH (hereafter termed heterozygous). Samples with somatic MUTYH mutations were considered separately. Samples without any MUTYH mutations were designated as WT.
COSMIC SBS18 Signature
In samples with at least five somatic single-base substitutions (SBSs), each assessable mutation was classified as one of 96 subtypes (six substitution classes with all possible permutations of bases immediately 5′ and 3′ of the mutated base). These mutations were resampled 1,000 times and then compared with the first 30 COSMIC SBS signatures using methods previously described in the study by Zehir et al.25
Tumor Mutational Burden
TMB was estimated as previously described.23 All synonymous and nonsynonymous short variants present at ≥5% variant AF were tallied. Potential germline variants were filtered out using published databases of known germline polymorphisms (including dbSNP, gnomAD, and ExAC), as well as by inferred germline status prediction via the SGZ algorithm. The final mutation number was divided by the total coding region (0.8 or 1.1 megabases for the FoundationOne and FoundationOne CDx assays, respectively). The TMB is reported in units of mutations per megabase of DNA (mut/Mb).
Results
Prevalence of MUTYH Genomic Alterations
In a cohort of tissue biopsies from 354,366 patients, 6,572 (1.9%) harbored a genomic alteration in MUTYH. Of these, 6,110 harbored a germline alteration: 119 with biallelic inheritance, nine with a germline alteration and a somatic alteration, and 5,982 with monoallelic inheritance. Of the 5,982 samples with monoallelic MUTYH mutations, 5,244 (88%) were predicted to be heterozygotes, while 738 (12%) were predicted to have lost the WT MUTYH allele (LOH; Figs 1A and 1B). The variant allele frequencies were highest in the LOH sample group and lowest in the group with somatic MUTYH mutations (Fig 1C).
The two most prevalent germline pathogenic MUTYH variants were p.G396D (rs36053993) and p.Y179C (rs34612342) and their distributions were similar in the sample groups with biallelic inheritance, heterozygous status, and LOH (Fig 1D). Other recurrent germline alterations included truncating mutations, splice site alterations, and rare pathogenic changes such as splice site X312 (rs77542170), p.E480del (rs587778541), p.A345Pfs*23 (rs587778536), p.R245H (rs140342925), and splice site X492 (rs140288388) (Fig 1E).
Relationship Between MUTYH Mutation Status and Mutation Signatures
As expected, tumor samples with biallelic germline pathogenic variants of MUTYH had a dominant COSMIC SBS18 signature, characteristic of reactive oxygen species damage that is left unrepaired owing to a defective BER pathway (Fig 2A). However, COSMIC SBS18 scores were also significantly higher in samples with a germline MUTYH pathogenic variant that had undergone LOH at the MUTYH locus in comparison with samples that were heterozygous for MUTYH (Fig 2A); there was no significant difference between samples that were heterozygous, had germline and somatic mutations, had only somatic mutations, or were WT at the locus (Fig 2B). The same trends were observed for COSMIC SBS36,26,27 another signature associated with the BER-deficient state (Appendix Fig A1). Examining the samples with one MUTYH germline variant that had undergone LOH, samples with the more deleterious Y179C had a higher median SBS18 score than those with G396D (Fig 2C), although the difference missed statistical significance.
Associations Between MUTYH Status, Chr 1p Loss, Genomic LOH, and TMB
Samples with MUTYH LOH also had a higher rate of Chr 1p loss (Fig 3A), suggesting that this is a common pathway by which MUTYH is inactivated. Genomic LOH (gLOH), which can be a consequence of homologous recombination deficiency, was higher in the sample group with LOH at the MUTYH locus, with a median gLOH of 10%, IQR of 5.3%-17%, while the heterozygous group had a median of 7.5%, IQR 3.5%-13% (P = 2.1E-18; Fig 3B), which did not differ significantly from WT. Thus, LOH at the MUTYH locus may arise through loss of an entire chromosome or homologous recombination repair deficiency without chromosome loss.
TMB was highest in the samples with germline and somatic variants or somatic variants only: median TMB 45 and 10 mutations/megabase, respectively (Fig 3C), suggesting that some of the somatic MUTYH variants are passenger mutations in high TMB samples. Nonetheless, 27% of samples with biallelic MUTYH variants met the 10 mutations/Mb threshold currently used as a pan-cancer biomarker predicting benefit from immune checkpoint inhibition.28 The sample groups with heterozygous germline variants or LOH had a rate of TMB ≥10, similar to the WT samples (17%-18%; Fig 3D).
Relationship Between MUTYH Mutation Status and Cancer Type
Tumor samples with biallelic germline pathogenic variants of MUTYH were predominantly CRCs (78/119, 66%), but also included some small intestine and other cancers (Fig 4A). We observed only six cases with inherited biallelic pathogenic MUTYH variants in over 38,000 breast cancers, consistent with the negative findings in a case control study29 that superseded initial reports of a possible increase in breast cancer risk in MUTYH-mutated patients.30 Similarly, there were only two biallelic patients in over 15,000 patients with prostate cancer (Appendix Table A1).
At the same time, samples with monoallelic germline MUTYH pathogenic variants and somatic LOH were not normally distributed across cancer types (Fig 4A). Although 104/738 (14%) samples with both a monoallelic pathogenic variant and LOH were CRCs, we did not observe an enrichment of this genotype in the CRC cases, nor was there an excess of monoallelic-only pathogenic variants in CRCs.
Cancer types showing an apparent excess of germline MUTYH heterozygous alterations included many endocrine tumors: pancreas islet cell tumors (3.3% with germline variants), adrenal gland (3.0%), thyroid medullary (2.4%), thymus (2.3%), as well as germ cell tumors (3.0%), carcinoids (2.9%), small intestine (2.6%), and bone sarcomas (2.2%) compared with the MUTYH germline variant frequency in CRC (2.0%), the overall cohort (1.8%), and the estimate of MUTYH heterozygosity in the general population as derived from gnomAD (1.3%; Appendix Table A1). In general, the prevalence of monoallelic MUTYH variants was low for hormonally driven cancers (breast, prostate, uterine, endometrial, and ovarian, 1.3%-1.7%).
Notably, the highest rates of germline MUTYH variants plus somatic LOH, with prevalence of over 2%, were found in adrenal gland cancers and pancreatic islet cell tumors (Fig 4A). Some of the cancer types with more prevalent LOH were those with higher rates of chromosome 1p loss, with pancreas islet cell tumors, adrenal gland tumors, bone sarcomas, and GI stromal tumors all having high rates than the cohort (Fig 4B).
Examining the LOH samples' SBS18 scores by cancer type, we also observed adrenal gland tumors and pancreas cell tumors having high median scores (0.83 and 0.74, respectively). Esophageal cancer and CRC had median scores of 0.22 and 0.13, respectively. Cancer types with typically high mutational burden such as melanoma and bladder cancer had low SBS18 scores (Fig 5).
Discussion
The findings from this large pan-cancer analysis suggest that LOH for MUTYH is seen in up to 12% of cancers originating in patients who carry a heterozygous germline pathogenic variant in MUTYH, an estimate that is in line with an earlier study on the basis of The Cancer Genome Atlas data.21 The majority of germline mutations in this study were G396D, which retains partial functional activity, and Y179C, which demonstrates severely compromised BER function.31 Both are European founder variants and together account for approximately 80% of MUTYH pathogenic variants in individuals of European ancestry.32 Although homozygosity for deleterious MUTYH variants is relatively rare, heterozygosity effects a considerably larger number of individuals and may predispose them to additional non-CRC malignancies.
Most studies of monoallelic MUTYH variants and cancer susceptibility have been hampered by relatively small data sets, owing both to the rarity of the genotype and the difficulty and expense of genotyping a sufficiently large number of patients for statistical significance. Studies on MUTYH heterozygosity and gene environment interactions are further limited, as capturing sufficiently granular data on potential exposures is difficult. However, MUTYH heterozygosity could, in tandem with other environmental exposures, increase oxidative DNA damage and increase DNA instability.
The SGZ algorithm employed here, by using tumor samples to infer germline mutation status, allows greater efficiency for larger population studies, and therefore may allow better understanding of how MUTYH variants affect tumorigenesis while also informing future clinical studies to target tumors with altered MUTYH function.
Although our data do not necessarily imply that monoallelic MUTYH variants are at a markedly increased susceptibility for cancer overall, it does suggest, as have other studies, that there may be an increase in susceptibility to some types of cancer, but it does not appear to play a role in breast or prostate cancer. Within these cancers, LOH at the MUTYH locus is likely a turning point in so far as the BER pathway is markedly affected, as reflected in the higher SBS18 scores in the absence of increased TMB.
One obvious weakness of our data set was that the patients were selected for biopsy and sequencing of their tumors, which may have introduced a selection bias to more advanced/metastatic cancers, implying a potential overestimate of MUTYH alteration abundance, and because of this, it is difficult to draw strong conclusions about the risk MUTYH carriers face. In addition, using the SGZ algorithm, we could not detect the presence of copy-neutral LOH.
Some of the apparently contradictory evidence for the relationship between monoallelic MUTYH variants and cancer risk may reflect that a single functional copy of MUTYH suffices under most circumstances to prevent BER deficiency and an accumulation of oxidative damage, while somatic loss of the second allele will lead to BER deficiency. Our data herein suggest that germline MUTYH carriers have a modest increase in susceptibility to some cancers, such as adrenal cancers, pancreatic neuroendocrine tumors (PanNETs), and potentially to cancers characterized by a high incidence of LOH at chromosome 1p.
Interestingly, germline MUTYH mutations have been reported in the literature as being associated with PanNETs, which in turn harbor increased mutation burden and more pronounced COSMIC SBS18 signatures.33 Some cancers, such as PanNETs34 as well as astrocytoma, are more prone to have loss of chromosome 1p.35 As our data confirm, chromosome 1p LOH (including copy-neutral LOH) happen at varying rates in different cancers and likely requires further study. The high rates of germline MUTYH alteration plus somatic LOH seen in adrenal gland tumors might be, in part, a consequence of the overall high rates of LOH in adrenal cancers. In our study, cancers with heterozygous MUTYH status had neither a significantly elevated TMB nor an increase in COSMIC 18 signature, consistent with a single functioning allele being sufficient for BER.30
Cancer cells depend on the BER pathway to overcome oxidative-induced DNA damage. Sensitivity and resistance to chemotherapies that act, at least in part, by causing oxidative DNA damage (eg, cisplatin, alkylating agents, and ionizing radiation) may theoretically be affected by alterations in BER function.36,37 An intact BER pathway is required to overcome oxaliplatin- and cisplatin-induced transcription arrest38 and BER inhibitors have been used as sensitizing agents to radiotherapy.28 It is also possible that BER deficiency could be exploited to intentionally increase tumor mutational burden by use of DNA-damaging agents.39 At the same time, it has been speculated on the basis of in vitro evidence that MUTYH may have evolved to be more than a BER enzyme and may be a multifunctional scaffold for rapid DNA damage response signaling,40 playing an important role in tandem with the mismatch repair pathway to determine cell fate in the presence of DNA damage.41
Evidence from Mutyh–/– knockout mice indicates that lack of functional Mutyh only modestly increases the mutation rate, and less so than when there is loss of mismatch repair. Our observations in MUTYH-deficient human cancers aligns with these findings from mouse models. Paradoxically, however, in mice, a double knockout of Msh2–/– and Mutyh–/– led to higher mutation rates, yet lower tumor volume burdens.42 Similar evidence from a case study in two siblings with MAP syndrome found that the individual with concurrent MSH6 mutation had a milder phenotype.43 This leaves the possibility that loss of MUTYH function may alter the progression of cancer in unpredictable ways depending on the concurrent presence or absence of an intact mismatch repair pathway and perhaps reflecting differences in the propensity for the resulting cancers to elicit a strong host immune response. There is much scope for clinical research to explore biologically informed approaches to the treatment of BER-deficient cancers, including both MAP-associated cancers and those arising in the context of an inherited pathogenic MUTYH variant and acquired LOH at that locus.
In conclusion, we present a large pan-cancer interrogation of MUTYH alterations in solid tumor malignancies using a real-world cohort and NGS analyses performed as part of routine clinical care. We show, unexpectedly, that biallelic MUTYH inactivation resulting from a germline heterozygous MUTYH mutation accompanied by somatic LOH occurs (at a low prevalence) in several noncolorectal malignancies including adrenal cancers, pancreatic islet cell tumors, and primary neurologic tumors (eg, PanNETs). Such cancers are characterized by deficient BER function manifesting as greater somatic mutation burden with significant contribution from the COSMIC SBS18 mutational signature, despite a rate of genomewide LOH below what is considered clinically actionable. This, in turn, may have therapeutic implications for checkpoint immunotherapy or synthetic lethality approaches that take advantage of defective base excision DNA repair.
Authors' Disclosures of Potential Conflicts of Interest
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Channing J. Paller
Consulting or Advisory Role: Dendreon, Omnitura, Exelixis, AstraZeneca
Research Funding: Lilly (Inst)
Travel, Accommodations, Expenses: Bayer
Hanna Tukachinsky
Employment: Foundation Medicine
Stock and Other Ownership Interests: Roche
Alexandra Maertens
Stock and Other Ownership Interests: Pfizer
Brennan Decker
Employment: Foundation Medicine
Stock and Other Ownership Interests: Roche, Vaccitech
Patents, Royalties, Other Intellectual Property: I am an inventor on numerous FMI-owned patent submissions related to research and development activities
Julian R. Sampson
Stock and Other Ownership Interests: GlaxoSmithKline
Jeremy P. Cheadle
Patents, Royalties, Other Intellectual Property: Patent holder for MUTYH variants. Previously received royalties from Myriad Genetics
Emmanuel S. Antonarakis
Honoraria: Sanofi, Dendreon (Inst), Medivation, Janssen Biotech, ESSA, Astellas Pharma, Merck, AstraZeneca, Clovis Oncology (Inst), Amgen, Bayer, Blue Earth Diagnostics, Bristol Myers Squibb/Celgene, Celgene (Inst), Constellation Pharmaceuticals, Curium Pharma, Lilly, Exact Sciences, Foundation Medicine, GlaxoSmithKline, InVitae, ISMAR Health Care, Tempus, Orion, AIkido Pharma, ClinicalMind, Z-Alpha, EcoR1 Capital
Consulting or Advisory Role: Sanofi, Dendreon, Janssen Biotech, ESSA, Merck, AstraZeneca, Clovis Oncology, Lilly, Bayer (Inst), Amgen, Astellas Pharma, Blue Earth Diagnostics, Bristol Myers Squibb/Celgene, Constellation Pharmaceuticals, Curium Pharma, Exact Sciences, Foundation Medicine, GlaxoSmithKline, InVitae, ISMAR Health Care, Medivation, Tempus, Orion, AIkido Pharma, Z-Alpha, EcoR1 Capital
Research Funding: Janssen Biotech (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Aragon Pharmaceuticals (Inst), Exelixis (Inst), Millennium (Inst), Genentech (Inst), Novartis (Inst), Astellas Pharma (Inst), Tokai Pharmaceuticals (Inst), Merck (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), Constellation Pharmaceuticals (Inst), Celgene, Clovis Oncology
Patents, Royalties, Other Intellectual Property: Co-inventor of a biomarker technology that has been licensed to Qiagen
Travel, Accommodations, Expenses: Sanofi, Dendreon, Medivation
No other potential conflicts of interest were reported.
Appendix
| Cancer Type | Total, n | Nongermline | Heterozygous | LOH | Germline/Nongermline | Biallelic | % MUTYH Mutation | Odds Ratio LOH v het | FDR_bh_ LOH v het |
|---|---|---|---|---|---|---|---|---|---|
| Pancreas islet cell | 976 | 2 | 9 | 22 | 0 | 0 | 3.50 | 17.872 | 0 |
| Adrenal gland | 617 | 1 | 5 | 13 | 0 | 0 | 3.18 | 18.788 | 0 |
| Bone sarcoma | 274 | 0 | 4 | 2 | 0 | 0 | 2.24 | 3.56 | 0.932 |
| GIST | 1,750 | 1 | 23 | 10 | 0 | 0 | 1.98 | 3.118 | 0.129 |
| Germ cell | 629 | 0 | 15 | 3 | 0 | 0 | 2.95 | 1.423 | 1 |
| Small intestine | 2,298 | 6 | 40 | 12 | 0 | 5 | 2.82 | 2.15 | 0.317 |
| PNS | 607 | 0 | 10 | 3 | 0 | 0 | 2.19 | 2.136 | 0.932 |
| Liver | 1,938 | 2 | 32 | 8 | 0 | 0 | 2.22 | 1.785 | 0.932 |
| CNS, nonglioma | 2,084 | 0 | 21 | 9 | 0 | 0 | 1.46 | 3.071 | 0.147 |
| Thyroid medullary | 390 | 0 | 8 | 1 | 0 | 0 | 2.36 | 0.888 | 1 |
| Appendix | 1,044 | 1 | 17 | 3 | 0 | 0 | 2.05 | 1.255 | 1 |
| CCA | 6,947 | 8 | 105 | 20 | 0 | 0 | 1.95 | 1.363 | 0.932 |
| Esophagus | 10,383 | 16 | 145 | 32 | 0 | 0 | 1.89 | 1.594 | 0.307 |
| Kidney | 6,280 | 6 | 90 | 18 | 1 | 1 | 1.88 | 1.432 | 0.932 |
| Thyroid | 2,937 | 1 | 41 | 9 | 0 | 1 | 1.80 | 1.567 | 0.932 |
| Peritoneum | 1,166 | 1 | 11 | 3 | 0 | 0 | 1.30 | 1.942 | 1 |
| Thymus | 401 | 0 | 8 | 1 | 0 | 0 | 2.30 | 0.888 | 1 |
| CRC | 46,006 | 56 | 704 | 104 | 1 | 78 | 2.09 | 1.058 | 1 |
| Salivary gland | 1,517 | 2 | 25 | 3 | 0 | 0 | 2.02 | 0.852 | 1 |
| Melanoma | 10,838 | 26 | 149 | 22 | 1 | 3 | 1.89 | 1.051 | 1 |
| Total | 354,366 | 462 | 5,244 | 738 | 9 | 119 | 1.89 | nan | nan |
| NSCLC | 67,991 | 111 | 989 | 129 | 2 | 7 | 1.85 | 0.911 | 1 |
| Stomach | 5,283 | 8 | 79 | 9 | 0 | 0 | 1.85 | 0.807 | 1 |
| Breast | 38,419 | 42 | 563 | 85 | 1 | 6 | 1.85 | 1.082 | 1 |
| HNSCC | 6,456 | 9 | 92 | 11 | 0 | 1 | 1.78 | 0.847 | 1 |
| Anus | 1,330 | 2 | 19 | 2 | 0 | 0 | 1.76 | 0.747 | 1 |
| Pancreas | 18,904 | 14 | 274 | 30 | 0 | 2 | 1.72 | 0.769 | 0.932 |
| Ovary | 21,802 | 22 | 305 | 39 | 0 | 3 | 1.72 | 0.903 | 1 |
| GI-neuro | 1,105 | 0 | 15 | 2 | 0 | 1 | 1.66 | 0.947 | 1 |
| Carcinoid | 821 | 0 | 22 | 1 | 0 | 0 | 2.88 | 0.322 | 1 |
| ACC | 1,372 | 1 | 28 | 2 | 0 | 0 | 2.31 | 0.506 | 1 |
| Fallopian tube | 2,139 | 4 | 40 | 2 | 0 | 0 | 2.20 | 0.354 | 0.932 |
| Cervix | 3,246 | 4 | 61 | 4 | 0 | 0 | 2.17 | 0.463 | 0.932 |
| Bladder | 8,162 | 17 | 134 | 10 | 0 | 0 | 2.01 | 0.524 | 0.459 |
| Glioma | 11,787 | 11 | 186 | 14 | 0 | 0 | 1.82 | 0.526 | 0.239 |
| Endometrial | 11,271 | 22 | 158 | 10 | 1 | 3 | 1.75 | 0.442 | 0.147 |
| Prostate | 15,875 | 14 | 237 | 9 | 0 | 2 | 1.68 | 0.261 | 0 |
| Gallbladder | 2,080 | 5 | 27 | 2 | 0 | 0 | 1.66 | 0.525 | 1 |
| Female genital | 1,053 | 0 | 15 | 1 | 0 | 1 | 1.64 | 0.473 | 1 |
| Uterus | 1,871 | 2 | 23 | 2 | 0 | 0 | 1.46 | 0.617 | 1 |
| Soft tissue sarcoma | 919 | 0 | 12 | 1 | 0 | 0 | 1.43 | 0.592 | 1 |
| SCLC | 3,825 | 0 | 52 | 2 | 0 | 0 | 1.43 | 0.271 | 0.469 |
| Skin | 1,681 | 10 | 27 | 0 | 1 | 0 | 2.31 | 0 | 0.515 |
| Leiomyosarcoma | 329 | 1 | 5 | 0 | 0 | 0 | 1.86 | 0 | 1 |
| Mesothelioma | 1,345 | 0 | 16 | 0 | 0 | 0 | 1.20 | 0 | 1 |
Abbreviations: ACC, adenoid cystic carcinoma; CCA, cholangiocarcinoma; CRC, colorectal cancer; FDR, false discovery rate (Benjamini-Hochberg corrected); GIST, GI stromal tumor; het, heterozygous; HNSCC, head and neck squamous cell carcinoma; LOH, loss of heterozygosity; NA, not applicable; NSCLC, non–small-cell lung cancer; PNS, peripheral nervous system; SCLC, small-cell lung cancer.
References
1.
Ames BN, Shigenaga MK, Hagen TM: Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90:7915-7922, 1993
2.
Nakabeppu Y, Tsuchimoto D, Yamaguchi H, et al: Oxidative damage in nucleic acids and Parkinson’s disease. J Neurosci Res 85:919-934, 2007
3.
Cheng KC, Cahill DS, Kasai H, et al: 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G → T and A → C substitutions. J Biol Chem 267:166-172, 1992
4.
Radak Z, Boldogh I: 8-Oxo-7,8-dihydroguanine: Links to gene expression, aging, and defense against oxidative stress. Free Radic Biol Med 49:587-596, 2010
5.
Kashfi SMH, Golmohammadi M, Behboudi F, et al: MUTYH the base excision repair gene family member associated with colorectal cancer polyposis. Gastroenterol Hepatol Bed Bench 6:S1-S10, 2013
6.
Thibodeau ML, Zhao EY, Reisle C, et al: Base excision repair deficiency signatures implicate germline and somatic MUTYH aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis. Cold Spring Harb Mol Case Stud 5:a003681, 2019
7.
Farrington SM, Tenesa A, Barnetson R, et al: Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet 77:112-119, 2005
8.
Al-Tassan N, Chmiel NH, Maynard J, et al: Inherited variants of MYH associated with somatic GC-->T: A mutations in colorectal tumors. Nat Genet 30:227-232, 2002
9.
Win AK, Dowty JG, Cleary SP, et al: Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology 146:1208-1211.e1-5, 2014
10.
Alexandrov LB, Nik-Zainal S, Wedge DC, et al: Signatures of mutational processes in human cancer. Nature 500:415-421, 2013
11.
Robinson PS, Thomas LE, Abascal F, et al: Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells. Nat Commun 13:3949, 2022
12.
Webb EL, Rudd MF, Houlston RS: Colorectal cancer risk in monoallelic carriers of MYH variants. Am J Hum Genet 79:768-771, 2006; author reply 771-772
13.
Breen KE, Katona BW, Catchings A, et al: An updated counseling framework for moderate-penetrance colorectal cancer susceptibility genes. Genet Med 24:2587-2590, 2022
14.
Ma X, Zhang B, Zheng W: Genetic variants associated with colorectal cancer risk: Comprehensive research synopsis, meta-analysis, and epidemiological evidence. Gut 63:326-336, 2014
15.
Thompson AB, Sutcliffe EG, Arvai K, et al: Monoallelic MUTYH pathogenic variants ascertained via multi-gene hereditary cancer panels are not associated with colorectal, endometrial, or breast cancer. Fam Cancer 21:415-422, 2022
16.
Win AK, Reece JC, Dowty JG, et al: Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH. Int J Cancer 139:1557-1563, 2016
17.
Ryland GL, Doyle MA, Goode D, et al: Loss of heterozygosity: What is it good for? BMC Med Genomics 8:45, 2015
18.
Cavenee WK, Dryja TP, Phillips RA, et al: Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305:779-784, 1983
19.
Merajver SD, Frank TS, Xu J, et al: Germline BRCA1 mutations and loss of the wild-type allele in tumors from families with early onset breast and ovarian cancer. Clin Cancer Res 1:539-544, 1995
20.
Nichols CA, Gibson WJ, Brown MS, et al: Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities. Nat Commun 11:2517, 2020
21.
Barreiro RAS, Sabbaga J, Rossi BM, et al: Monoallelic deleterious MUTYH germline variants as a driver for tumorigenesis. J Pathol 256:214-222, 2022
22.
Frampton GM, Fichtenholtz A, Otto GA, et al: Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 31:1023-1031, 2013
23.
Milbury CA, Creeden J, Yip W-K, et al: Clinical and analytical validation of FoundationOne®CDx, a comprehensive genomic profiling assay for solid tumors. PLoS One 17:e0264138, 2022
24.
Sun JX, He Y, Sanford E, et al: A computational approach to distinguish somatic vs. germline origin of genomic alterations from deep sequencing of cancer specimens without a matched normal. PLoS Comput Biol 14:e1005965, 2018
25.
Zehir A, Benayed R, Shah RH, et al: Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 23:703-713, 2017
26.
Viel A, Bruselles A, Meccia E, et al: A specific mutational signature associated with DNA 8-oxoguanine persistence in MUTYH-defective colorectal cancer. EBioMedicine 20:39-49, 2017
27.
Georgeson P, Pope BJ, Rosty C, et al: Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers. Gut 70:2138-2149, 2021
28.
Grundy GJ, Parsons JL: Base excision repair and its implications to cancer therapy. Essays Biochem 64:831-843, 2020
29.
Out AA, Wasielewski M, Huijts PEA, et al: MUTYH gene variants and breast cancer in a Dutch case–control study. Breast Cancer Res Treat 134:219-227, 2012
30.
Nielsen M, Franken PF, Reinards THCM, et al: Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Genet 42:e54, 2005
31.
Ali M, Kim H, Cleary S, et al: Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology 135:499-507, 2008
32.
Leoz ML, Carballal S, Moreira L, et al: The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management. Appl Clin Genet 8:95-107, 2015
33.
Scarpa A, Chang DK, Nones K, et al: Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 543:65-71, 2017
34.
Lawrence B, Blenkiron C, Parker K, et al: Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer. NPJ Genom Med 3:18, 2018
35.
Zhang C, Yu R, Li Z, et al: Comprehensive analysis of genes based on chr1p/19q co-deletion reveals a robust 4-gene prognostic signature for lower grade glioma. Cancer Manag Res 11:4971-4984, 2019
36.
Caiola E, Salles D, Frapolli R, et al: Base excision repair-mediated resistance to cisplatin in KRAS(G12C) mutant NSCLC cells. Oncotarget 6:30072-30087, 2015
37.
Raetz AG, Banda DM, Ma X, et al: The DNA repair enzyme MUTYH potentiates cytotoxicity of the alkylating agent MNNG by interacting with abasic sites. J Biol Chem 295:3692-3707, 2020
38.
Slyskova J, Sabatella M, Ribeiro-Silva C, et al: Base and nucleotide excision repair facilitate resolution of platinum drugs-induced transcription blockage. Nucleic Acids Res 46:9537-9549, 2018
39.
Cao Y, Ma Y, Yu J, et al: Favorable response to immunotherapy in a pancreatic neuroendocrine tumor with temozolomide-induced high tumor mutational burden. Cancer Commun 40:746-751, 2020
40.
Raetz AG, David SS: When you’re strange: Unusual features of the MUTYH glycosylase and implications in cancer. DNA Repair 80:16-25, 2019
41.
Oka S, Leon J, Tsuchimoto D, et al: MUTYH, an adenine DNA glycosylase, mediates p53 tumor suppression via PARP-dependent cell death. Oncogenesis 4:e142, 2015
42.
Russo MT, De Luca G, Casorelli I, et al: Role of MUTYH and MSH2 in the control of oxidative DNA damage, genetic instability, and tumorigenesis. Cancer Res 69:4372-4379, 2009
43.
van Puijenbroek M, Nielsen M, Reinards THCM, et al: The natural history of a combined defect in MSH6 and MUTYH in a HNPCC family. Fam Cancer 6:43-51, 2007
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JCO Precision Oncology
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© 2024 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/
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Published online: February 23, 2024
Authors
Author Contributions
Conception and design: Channing J. Paller, Hanna Tukachinsky, Alexandra Maertens, Brennan Decker, Emmanuel S. Antonarakis
Financial support: Channing J. Paller
Administrative support: Channing J. Paller
Provision of study materials or patients: Channing J. Paller, Emmanuel S. Antonarakis
Collection and assembly of data: Channing J. Paller, Brennan Decker, Emmanuel S. Antonarakis
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
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Pan-Cancer Interrogation of MUTYH Variants Reveals Biallelic Inactivation and Defective Base Excision Repair Across a Spectrum of Solid Tumors. JCO Precis Oncol 8, e2300251(2024).
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