Bill Paseman — Clinical & Genomic Summary

1 — Primary Diagnoses

Papillary Type 1 Renal Cell Carcinoma (p1RCC) NED

ICD-10	C64.2
Stage	pT3aN0M0
Size	5.6 cm, left kidney
Grade	Fuhrman 2
Diagnosed	2014-02-20, Johns Hopkins
Surgery	Left nephrectomy 2014-03-24 — negative margins
Discovery	Incidental — DVT workup
NED Since	2014-03-31 — confirmed through 2022

Intracranial Meningioma (WHO Grade I presumed) Surveillance

ICD-10	D32.0
Location	Near lateral ventricles
Diagnosed	2014-02-20, Johns Hopkins
Discovery	Incidental — same imaging as RCC
Growth rate	~0.5 mm/year
Volume	2.43 cc (2023-09-11)
Treatment	None to date
Metastasis?	NOT an RCC metastasis — neurosurgeon consensus

Meningioma Size Progression

Date	Dimensions (cm)	Volume (cc)	Institution
2014-02-20	1.0 × 1.2 × 0.8	—	Johns Hopkins
2015-12-05	1.0 × 1.3 × 1.1	0.96	UCSD
2022-03-11	1.8 × 1.9 × 1.5	—	Sutter
2022-03-18	1.8 × 1.6 × 1.5	2.51	UCSD
2022-09-23	1.8 × 1.4 × 1.6	2.66	UCSD
2023-09-11	1.8 × 1.5 × 1.6	2.43	UCSD

2 — Comorbidities (16 Conditions)

#	Condition	ICD-10	Status
1	Deep Vein Thrombosis (DVT), recurrent	I82.40	Chronic — aspirin 81mg (Xarelto/Eliquis preferred)
2	Intracranial Meningioma	D32.0	Cross-reference to primary diagnoses
3	Thoracic Aortic Ectasia	I77.810	Stable — 4.2–4.3 cm ascending aorta, serial imaging
4	Hyperhomocysteinemia with MTHFR C677T	E72.11	Active — B12/folate supplementation ongoing
5	Obstructive Sleep Apnea, very severe	G47.33	Active
6	Bradycardia	R00.1	Active — resting HR consistently <60 BPM
7	Benign Paroxysmal Positional Vertigo (BPPV)	H81.10	Active — contributor to balance disturbances
8	Peripheral Neuropathy, mild	G60.9	Active — B12 deficiency excluded; maintain B12 >450 pg/mL
9	Gout	M10.9	Active — uric acid 8.7 mg/dL (ref <6.0)
10	Amblyopia (Strabismus)	H53.00	Chronic stable — lifelong since childhood
11	Lumbar Disc Bulging with Radiculopathy	M51.16	Active — MRI 2022-04-19; benign vertebral hemangiomas
12	Thyroid Nodule, benign + Low Free T3	E04.1	Surveillance — 2.8 cm TR4 nodule; Free T3 2.8–2.9 (ref 4.4)
13	Rosacea	L71.9	Chronic — patient notes possible thyroid cancer association
14	Lipoprotein(a) Elevation	—	Active — Lp(a) 106 mg/dL (ref <30); no intervention documented
15	Gum Disease / Microbiome Dysbiosis	—	Historical — unclear current status
16	Left Foot Weakness	—	Chronic stable — since 1992, unable to stand on toes

3 — Somatic Tumor Analysis: RNA Expression Key Findings

Data Source

RNA-seq on archived 2014 nephrectomy tissue vs. matched normal kidney. Units: RPKM. ~18,000 genes analyzed. Global tumor expression is lower than normal — relative patterns within tumor are the primary signal.

Gene	Normal RPKM	Tumor RPKM	Log2 FC	Priority	Clinical Significance
PDGFRA	9.56	23.33	+1.29 ↑	HIGHEST	Triple-positive: RNA overexpression + DNA amplification (2.3x CNV) + somatic splice/missense mutations. Top actionable target. Imatinib, avapritinib, sunitinib.
ROS1	0.0	0.36	Tumor-only	HIGH	Absent in normal, present in tumor. Somatic amplification (2.0x CNV) + stop-gained variant. FISH/fusion panel needed. ROS1 inhibitors: crizotinib, entrectinib, lorlatinib.
FH (Fumarate Hydratase)	2758	36.39	−6.24 ↓ (75-fold)	HIGH	Strongest RNA signal. 11 high-impact somatic variants at DNA level. FH-deficient RCC responds to bevacizumab + erlotinib. HLRCC (hereditary) ruled out — germline FH clean.
MET	3742	12.16	−8.27 ↓ (307-fold)	HIGH	MET PARADOX: DNA amplified (2.3x) but RNA silenced (307-fold down). No exon 14 skipping. Standard p1RCC assumption of MET-driven disease does NOT apply here. MET inhibitors are low priority.
EPAS1 (HIF-2α)	514.56	139.14	−1.89 ↓	HIGH	Somatically DELETED at DNA (0.69x CNV) + reduced RNA. Belzutifan (HIF-2α inhibitor) has NO target here — gene is already lost. Belzutifan is CONTRAINDICATED.
VHL	291.04	14.54	−4.32 ↓	MEDIUM	RNA reduced. CNV shows slight gain (1.34x), not deletion — VHL-loss-driven disease not strongly supported. SnpEff high-impact count (77) inflated by multi-transcript artifact.
SETD2	307.69	13.46	−4.51 ↓	MEDIUM	Consistent with p1RCC molecular subtype. 5 high-impact somatic variants (2 stop-gains, 1 splice). EZH2 inhibition may be relevant.
CDKN2A	5.54	0.37	−3.90 ↓	MEDIUM	Loss enables CDK4/6-driven proliferation. CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) investigational in RCC. May explain elevated APOBEC signature.
BAP1	242.88	30.54	−2.99 ↓	MEDIUM	Loss associated with aggressive behavior and immunotherapy response prediction.
KDM5C	406.31	18.16	−4.48 ↓	LOW-MED	X-linked histone demethylase; frequently altered in papillary RCC. Consistent with p1RCC molecular signature.
TFE3	457.25	21.46	−4.41 ↓	LOW	Downregulation argues against TFE3-fusion (Xp11 translocation) RCC — consistent with p1RCC classification.

4 — Somatic Copy Number Variants (CNV)

Method

T1_1A tumor CNV cross-referenced against WBA germline baseline to confirm somatic origin. Copy ratio 1.0 = diploid normal.

Actionable Amplifications

Gene	Copy Ratio	Priority	Significance
PDGFRA	2.32x	HIGHEST	Triple-positive convergence (DNA + RNA + somatic mutations). Strongest actionable target in this tumor.
MET	2.31x	HIGH	MET paradox — amplified DNA, silenced RNA (307-fold). Epigenetic silencing (promoter methylation) suspected. MET inhibitor efficacy uncertain.
ROS1	1.99x	HIGH	Amplification + tumor-specific RNA + stop-gained somatic variant. Fusion not confirmed — SV file needed.
MTOR	1.66x	MEDIUM	Supports mTOR inhibitor use (everolimus, temsirolimus — both approved in RCC).
PIK3CA	1.64x	MEDIUM	PI3K/AKT/mTOR axis amplification. Combined with MTOR gain — recurrent pathway theme.

Actionable Deletions

Gene	Copy Ratio	Priority	Significance
EPAS1 (HIF-2α)	0.69x	HIGH	Deleted at DNA + reduced RNA. Belzutifan (HIF-2α inhibitor) has no target — strongly CONTRAINDICATED for this patient.
TFEB	0.71x	LOW-MED	Argues against TFEB-translocation RCC subtype — consistent with p1RCC classification.
PDGFRB	0.75x	LOW	B-receptor deleted while A-receptor (PDGFRA) is amplified — selective PDGFRA pathway dependence.

Other Notable CNV

Gene	Copy Ratio	Type	Note
NF1	1.86x	Amplification	Unusual for tumor suppressor — significance unclear
NF2	1.77x	Amplification	Unusual for tumor suppressor — significance unclear
RB1	1.60x	Gain	DNA gain; somatic splice mutations from SNV data are likely loss-of-function mechanism
VHL	1.34x	Slight gain	Gain, not loss — argues against VHL-driven disease; SNV count inflated by transcript artifact
SETD2	1.34x	Slight gain	DNA gain; somatic point mutations are loss-of-function mechanism

Note: ARID1A has a germline CNV event — its 4 somatic stop-gains from SNV data may still be meaningful but the CNV component is constitutional.

5 — Mutational Signatures (SBS 96-Channel Analysis)

Method

1,380 EVS≥15 PASS somatic SNVs from Strelka2 (somatic.snvs.snpeff.vcf.gz). Trinucleotide context from Ensembl GRCh37 REST API. 100% reference concordance confirming hg19 alignment.

6-Type Substitution Distribution

C>T

34.3%

474 variants — dominant; age-related (SBS1+SBS5)

T>C

18.4%

254 variants — clock-like (SBS5)

C>A

14.4%

199 variants — oxidative damage signal

T>A

13.8%

191 variants

T>G

9.8%

135 variants

C>G

9.2%

127 variants — APOBEC-adjacent

COSMIC Signature Calls

Signature	Name	Status	Evidence	Interpretation
SBS1	Age — CpG deamination	Confirmed	8.3% C>T at CpG	Age-appropriate. NOT elevated. Consistent with ~60-year-old at diagnosis.
SBS5	Clock-like / aging	Confirmed	C>T 34.3% + T>C 18.4%	Second universal clock-like signature. Normal aging as dominant mutagenic background.
SBS2/SBS13	APOBEC	Elevated	11.7% C>T/C>G in TC context	APOBEC3A/3B activity — associated with CDKN2A loss (present in this tumor). Known RCC association. Cellular stress response to oncogenic transformation.
SBS6/15/21/26	MMR deficiency	ABSENT	T>C = 18.4% (threshold: 30–40%+)	Lynch syndrome and MMR deficiency ruled out somatically. Corroborates clean germline MLH1/MSH2/MSH6/PMS2.

Tumor Mutational Burden (TMB)

Subset	Variant Count	Estimated TMB	Interpretation
All PASS variants	~839,000	~280 mut/Mb	Inflated — pipeline calibration artifact (EVS score capping suggests this is an overestimate)
EVS ≥15 subset	~29,755	~10 mut/Mb	Likely true range — moderately elevated; not hypermutator (>100 mut/Mb)

Implication for MTHFR Hypothesis

SBS1 at 8.3% is age-appropriate and not elevated. If MTHFR C677T homozygous were causing severe constitutional hypomethylation (reduced 5-methylcytosine), there would be fewer methylated cytosines available to deaminate — paradoxically suppressing SBS1, not elevating it. The observed SBS1 level weakens the MTHFR-as-shared-driver hypothesis for the RCC + meningioma co-occurrence.

6 — Microsatellite Instability (MSI) Analysis

MSI Call: MSS — Microsatellite Stable

0.90 somatic indels/Mb. Well below the MSI-H threshold of >10 indels/Mb. Lynch syndrome excluded somatically.

Metric	Value	Reference
PASS somatic indels	2,686	—
Insertions	1,071	—
Deletions	1,615	—
Insertion:Deletion ratio	0.66 (deletion-dominant)	Normal pattern
Somatic indel rate	0.90 indels/Mb	MSS <2 / MSI-L 2–10 / MSI-H >10
Long homopolymer indels	45.8%	Normal distribution

Clinical implication: MSS tumors respond poorly to checkpoint inhibitor monotherapy (pembrolizumab/nivolumab). Combination approaches or alternative strategies preferred if systemic therapy is needed.

7 — Germline Genetics

Source

BGI BGISEQ-500 whole blood sequencing (WBA), 90x coverage, hg19. Files: WBA.snp.cds_annot.csv.gz, WBA.indel.cds_annot.csv.gz, WBA.cnv.gene.csv.

Clinically Significant Germline Variants

Gene	Variant	rsID	Zygosity	Pop. Freq.	Assessment
MTHFR	p.Ala222Val / c.665C>T (C677T)	rs1801133	Homozygous	24.5%	FUNCTIONAL — decreased enzyme activity, elevated homocysteine, increased CV/thrombosis/stroke risk. Confirmed by Labcorp 2022. Modest kidney cancer association. Not pathogenic per ACMG criteria but clinically significant.
ATM	p.Asp1853Asn / c.5557G>A	rs1801516	Heterozygous	6.7%	Low-penetrance variant. SIFT 0.23 tolerated, PolyPhen2 0.015 benign. Not pathogenic in isolation. Caution with radiation therapy if ever indicated.
TP53	p.Pro72Arg / c.215C>G	rs1042522	Homozygous (Arg/Arg)	54.3%	Common population polymorphism. Not pathogenic.
BRCA1	p.Ser1634Gly / c.4900A>G	rs1799966	Heterozygous	35.6%	Common polymorphism. PolyPhen2 benign despite SIFT flagging. Not pathogenic.
BRCA2	p.Asn372His / c.1114A>C	rs144848	Homozygous	24.9%	Common polymorphism. Not pathogenic.

Extended Panel — Meningioma Predisposition Genes

Gene	Syndrome	Result	Status
SMARCE1	Multiple spinal meningiomas / clear cell meningioma	CLEAN — no variants	Ruled Out
SMARCB1	Schwannomatosis type 1 / rhabdoid tumor predisposition	CLEAN — no variants	Ruled Out
LZTR1	Schwannomatosis type 2	2 synonymous variants (17–29% pop. freq.) — low impact only	Ruled Out
SUFU	Meningioma + medulloblastoma predisposition	CLEAN — no variants	Ruled Out
PTCH1	Gorlin syndrome	P1315L (rs357564, 40% pop. freq.) — common polymorphism only	Ruled Out

Extended Panel — Lynch Syndrome / MMR Genes

Gene	Result	Status
MLH1	CLEAN — no variants	Lynch Ruled Out
MSH2	CLEAN — no variants	Lynch Ruled Out
MSH6	4 synonymous variants (Arg62Arg, Pro92Pro, Asp180Asp, Tyr214Tyr) — all 7–14% pop. freq., low impact	Lynch Ruled Out
PMS2	K541E (rs2228006, 88% pop. freq.) + 1 synonymous — both common	Lynch Ruled Out

8 — What Has Been Eliminated as a Cause

Hereditary Cancer Syndromes — All Definitively Ruled Out

Syndrome	Genes Checked	Basis for Exclusion	Status
NF2 (Neurofibromatosis type 2)	NF2	Clean germline SNV + indel in WBA data	Ruled Out
NF2 extended panel (schwannomatosis)	SMARCE1, SMARCB1, LZTR1, SUFU	All clean or common polymorphisms only	Ruled Out
Gorlin syndrome	PTCH1	P1315L is 40% population polymorphism — not pathogenic	Ruled Out
BAP1 cancer predisposition syndrome	BAP1	Clean germline SNV + indel in WBA data	Ruled Out
HLRCC / FH hereditary syndrome	FH	Germline SNV, indel, AND CNV all negative. Somatic FH loss in tumor is a purely acquired event. No cascade family testing required.	Ruled Out
Lynch syndrome / MMR deficiency	MLH1, MSH2, MSH6, PMS2	Dual exclusion: (1) Germline — all 4 MMR genes clean or synonymous-only. (2) Somatic — absent SBS6/15/21/26 signature (T>C = 18%, not 30–40%+) AND MSS call (0.90 indels/Mb).	Ruled Out — Germline + Somatic
Hereditary BRCA1/2 syndrome	BRCA1, BRCA2	Only common population polymorphisms — no pathogenic variants	Ruled Out
Germline MET predisposition	MET	No germline CNV — any somatic MET amplification is acquired	Ruled Out

Treatment Targets Eliminated or Contraindicated

Target / Drug	Reason Eliminated	Verdict
Belzutifan (HIF-2α inhibitor)	EPAS1 (HIF-2α) is somatically deleted (0.69x CNV) and transcriptionally reduced. The drug's target is already gone at both DNA and RNA levels.	CONTRAINDICATED
MET-targeted inhibitors as primary therapy (tepotinib, capmatinib, selective MET cabozantinib)	MET RNA silenced 307-fold despite DNA amplification. No exon 14 skipping. No high-confidence oncogenic MET variants. Cabozantinib responses, if any, would be via VEGFR2/AXL/RET off-target activity, not MET.	Low Priority
Checkpoint monotherapy (pembrolizumab, nivolumab alone)	MSS tumor (0.90 indels/Mb). Single-agent PD-1/PD-L1 inhibitors have poor response rates in MSS RCC. Combination approaches needed.	Not Preferred
VHL-pathway-centric treatment assumption	VHL CNV shows slight gain (1.34x), not deletion. SnpEff variant count inflated. VHL-loss-driven disease not strongly supported by multi-omic data.	Weak Evidence

Standard p1RCC Assumption Broken: MET Is Not the Driver

MET Paradox

The textbook model for papillary Type 1 RCC is MET amplification/activation as the primary oncogenic driver. This tumor breaks that model. MET DNA is amplified (2.31x copy ratio) but transcriptionally silenced (307-fold RNA decrease vs. matched normal). No exon 14 skipping. Only low-confidence, low-VAF (<3%) splice variants at non-canonical sites. Most likely mechanism: promoter hypermethylation silencing an amplified locus. MET promoter methylation analysis would confirm this. Treating this tumor as standard MET-driven p1RCC would lead to incorrect treatment prioritization.

9 — p1RCC + Meningioma Co-occurrence: Candidate Mechanisms

Mechanism	Confidence	Evidence For	Evidence Against / Weaknesses
Coincidental co-occurrence of two sporadic age-related tumors	Cannot Be Excluded — Default	Both p1RCC and meningioma peak in males in their 50s–60s. No unifying syndromic driver identified after comprehensive germline investigation across >15 genes.	—
MTHFR C677T homozygous — constitutional methylation cycle impairment leading to multi-tissue epigenetic instability	Plausible but Weakened	Homozygous MTHFR C677T confirmed. Elevated homocysteine corroborates impaired remethylation. Epidemiologic data: modest OR (~1.5–2x) for meningioma in some studies. Operates constitutionally across all tissues.	SBS1 at 8.3% is age-appropriate, NOT elevated — if severe hypomethylation were present, fewer methylated CpGs would be available to deaminate, paradoxically suppressing SBS1. Blood EPIC methylation array would be definitive test.
ATM D1853N heterozygous — impaired DNA double-strand break repair	Weak Contributing Factor	ATM D1853N confirmed in germline. ATM haploinsufficiency reduces DSB repair fidelity over decades.	Primary ATM-related cancer risk is breast/pancreatic/hematologic — not a clean fit for RCC or meningioma. Missense variant, not truncating. Background contributing factor only.

Bottom Line

No single hereditary syndrome explains both tumors. NF2, BAP1, FH, SMARCE1, SMARCB1, LZTR1, SUFU, PTCH1, MLH1, MSH2, MSH6, and PMS2 are all clean. The most parsimonious explanation after full genomic investigation is coincidental co-occurrence of two sporadic age-related tumors, with MTHFR C677T providing at most a modest constitutional background predisposition (weakened by normal SBS1 levels). Family cascade germline testing is NOT indicated — no pathogenic variant that would confer heritable meningioma risk to first-degree relatives has been found.

10 — Actionable Priorities If Recurrence Occurs

Priority	Target	Evidence Basis	Candidate Agents
1 — HIGHEST	PDGFRA	Triple-positive convergence: DNA amplification (2.32x) + RNA overexpression (2.4-fold) + somatic splice/missense mutations. Strongest multi-omic signal in this tumor.	Imatinib, avapritinib, sunitinib (partial PDGFRA activity)
2	FH-deficient RCC regimen	75-fold RNA silencing + 11 high-impact somatic DNA variants. Strongest RNA signal. HLRCC ruled out (somatic event only).	Bevacizumab + erlotinib (preferred regimen for FH-deficient RCC)
3	ROS1	Somatic amplification (2.0x CNV) + tumor-specific RNA expression + stop-gained somatic variant. Fusion not yet confirmed.	Crizotinib, entrectinib, lorlatinib — after FISH/fusion panel confirmation
4	MTOR/PI3K axis	MTOR amplification (1.66x) + PIK3CA amplification (1.64x). Convergent PI3K/AKT/mTOR pathway amplification.	Everolimus, temsirolimus (both approved in RCC); alpelisib (PI3K)
5	CDK4/6 pathway	CDKN2A loss + RB1 somatic splice mutations + CDK4/CDK6 expressed in tumor (42.38 / 5.05 RPKM).	Palbociclib, ribociclib, abemaciclib (investigational in RCC)

Critical Caveat: These Findings Are Not in the Institutional EHR

All genomic analysis above lives in a patient-maintained shadow record. A treating oncologist at Johns Hopkins, UCSF, or Stanford encountering a recurrence would have access only to the basic pathology (pT3aN0M0, Fuhrman grade 2, p1RCC). They would have no access to the PDGFRA triple-positive finding, MET paradox, EPAS1 deletion, or any of the AI-derived treatment prioritization unless it is explicitly shared. Practical near-term fix: Order a CLIA-certified clinical genomic panel (FoundationOne CDx, Tempus xT, or Caris MI Profile) on archived 2014 nephrectomy tissue to create an institutional genomic report that enters the EHR.